The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries.
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- See Evidence submitted by expert panel for details.
Variant: NM_007123.5(USH2A):c.4338_4339delCT (p.Cys1447Glnfs)
CA252228
2353 (ClinVar)
Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 5fc296e5-bbfb-4876-ace3-0e1618efc366
HGVS expressions
NM_007123.5:c.4338_4339delCT
NM_007123.5(USH2A):c.4338_4339delCT (p.Cys1447Glnfs)
NC_000001.11:g.216190284_216190285del
CM000663.2:g.216190284_216190285del
NC_000001.10:g.216363626_216363627del
CM000663.1:g.216363626_216363627del
NC_000001.9:g.214430249_214430250del
NG_009497.1:g.238116_238117del
NM_007123.5:c.4338_4339del
NM_206933.2:c.4338_4339del
NM_206933.3:c.4338_4339del
ENST00000307340.7:c.4338_4339del
ENST00000366942.3:c.4338_4339del
Pathogenic
The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"Met criteria codes 5
PVS1
PM3_Very Strong
PP1_Moderate
PP4
PM2
Not Met criteria codes 18
BA1
BP7
BP5
BP4
BP3
BP2
BS2
BS1
BS4
PP3
PM5
PM4
PM1
PM6
PS1
PS3
PS4
PS2
Evidence Links 7
Expert Panel
Evidence submitted by expert panel
Hearing Loss VCEP
The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID: 20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4.
Met criteria codes
PVS1
This variant causes a stop codon in the last exon of the shorter biological transcript but we consider the long transcript to be biologically relevant which means this will cause a truncated/absent protein.
RS: The variant occurs in the penultimate exon of the shorter transcript, but is not alternatively spliced, and therefore is predicted to lead to a truncated protein.
PM3_Very Strong
This can be upgraded to PM3_VS as there are several instances of this being observed in a homozygous state as well as a compound heterozygous state with variants such as the C759F variant which is a LP/P variant.
This study identified 3 USH2 patients with the Cys1447fs variant that also had the Cys759Phe variant which has been classified by several labs in ClinVar (including LMM who cite 14 publications) as Pathogenic.
PubMed:18641288
Used genotyping assays to identify the c.4338_4339delCT variant in 4/9 homozygous probands from Canada. Observed no carriers of the variant in 207 healthy controls from Quebec. Additionally, there was one French Canadian patient from Quebec who was compound heterozygous for the c.4338_4339delCT and c.2299delG variants with Usher syndrome.
PubMed:18665195
Homozygous c.4353-54delCT is mapped to be equivalent to this variant by HGMD and it was found to be present in a homozygous state in III-1 and III-3 in family #536. There were 2 unaffected individuals as well and the non consanguineous parents were healthy.
PubMed:9624053
This study identified another 2 French Canadian patients with the p.C1447QfsX variant who were homozygous for the variant but one also had a p.R56PfsX het. variant in PDZD7 which seemed to exacerbate the retinal phenotype.
PubMed:20440071
This study also identified 2 USH2 patients with the Cys1447fs variant in trans with the C759F variant which is classified as pathogenic by the LMM in ClinVar. There was also a homzygote. The variant was also identified in a heterozygous state in 4 cases of autosomal recessive RP but these patients didn't appear to have any other USH2A mutations.
PubMed:15325563
PP1_Moderate
There are a 2 families that both have 2 affected and 2 unaffected individuals documented which counts as 2 affected segregations and 4 unaffected segregations total across the two families which allows the application of PP1_S (LOD = 1.7).
RS: I'm not sure I would include the Eudy family, because it is unclear whether everyone was sequenced in the family. Therefore, PP1_Moderate would be applied (LOD:1.45)
Homozygous c.4353-54delCT is mapped to be equivalent to this variant by HGMD and it was found to be present in a homozygous state in III-1 and III-3 in family #536. There were 2 unaffected individuals as well and the non consanguineous parents were healthy. This counts as 1 affected segregation and 2 unaffected segs
PubMed:9624053
The homozygous C1447QfsX variant segregated into 2 affected siblings who were apparently the result of a non consanguineous marriage. One of the individuals also had a heterozygous de novo mutation in the PDZD7 R56PfsX which seemed to exacerbate the retinal phenotype. There were also two other unaffected individuals (1 het 1 WT/WT). This counts as 1 affected segregation and 2 unaffected segs
PubMed:20440071
PP4
Several Usher patients meeting this phenotypic requirement for USH2A
Used genotyping assays to identify the c.4338_4339delCT variant in 4/9 homozygous probands from Canada. Observed no carriers of the variant in 207 healthy controls from Quebec. Additionally, there was one French Canadian patient from Quebec who was compound heterozygous for the c.4338_4339delCT and c.2299delG variants with Usher syndrome.
PubMed:18665195
This study identified 3 USH2 patients with the Cys1447fs variant that also had the Cys759Phe variant which has been classified by several labs in ClinVar (including LMM who cite 14 publications) as Pathogenic.
PubMed:18641288
Homozygous c.4353-54delCT is mapped to be equivalent to this variant by HGMD and it was found to be present in a homozygous state in III-1 and III-3 in family #536. There were 2 unaffected individuals as well and the non consanguineous parents were healthy.
PubMed:9624053
This study identified another 2 French Canadian patients with the p.C1447QfsX variant who were homozygous for the variant but one also had a p.R56PfsX het. variant in PDZD7 which seemed to exacerbate the retinal phenotype.
PubMed:20440071
This study also identified 2 USH2 patients with the Cys1447fs variant in trans with the C759F variant which is classified as pathogenic by the LMM in ClinVar. There was also a homzygote. The variant was also identified in a heterozygous state in 4 cases of autosomal recessive RP but these patients didn't appear to have any other USH2A mutations.
PubMed:15325563
PM2
Variant present in 1/111250 (0.0009%) European (non-Finnish) alleles in gnomAD.
RS: Under current guidelines, this would reach PM2_Moderate (</= 0.007%)
Not Met criteria codes
BA1
Variant present in 1/111250 (0.0009%) European (non-Finnish) alleles in gnomAD.
RS: Under current guidelines, this would reach PM2_Moderate (</= 0.007%)
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
This study identified 3 USH2 patients with the Cys1447fs variant that also had the Cys759Phe variant which has been classified by several labs in ClinVar (including LMM who cite 14 publications) as Pathogenic.
PubMed:18641288
Used genotyping assays to identify the c.4338_4339delCT variant in 4/9 homozygous probands from Canada. Observed no carriers of the variant in 207 healthy controls from Quebec. Additionally, there was one French Canadian patient from Quebec who was compound heterozygous for the c.4338_4339delCT and c.2299delG variants with Usher syndrome.
PubMed:18665195
Homozygous c.4353-54delCT is mapped to be equivalent to this variant by HGMD and it was found to be present in a homozygous state in III-1 and III-3 in family #536. There were 2 unaffected individuals as well and the non consanguineous parents were healthy.
PubMed:9624053
This study identified another 2 French Canadian patients with the p.C1447QfsX variant who were homozygous for the variant but one also had a p.R56PfsX het. variant in PDZD7 which seemed to exacerbate the retinal phenotype.
PubMed:20440071
This study also identified 2 USH2 patients with the Cys1447fs variant in trans with the C759F variant which is classified as pathogenic by the LMM in ClinVar. There was also a homzygote. The variant was also identified in a heterozygous state in 4 cases of autosomal recessive RP but these patients didn't appear to have any other USH2A mutations.
PubMed:15325563
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
Variant present in 1/111250 (0.0009%) European (non-Finnish) alleles in gnomAD.
RS: Under current guidelines, this would reach PM2_Moderate (</= 0.007%)
BS4
Homozygous c.4353-54delCT is mapped to be equivalent to this variant by HGMD and it was found to be present in a homozygous state in III-1 and III-3 in family #536. There were 2 unaffected individuals as well and the non consanguineous parents were healthy. This counts as 1 affected segregation and 2 unaffected segs
PubMed:9624053
The homozygous C1447QfsX variant segregated into 2 affected siblings who were apparently the result of a non consanguineous marriage. One of the individuals also had a heterozygous de novo mutation in the PDZD7 R56PfsX which seemed to exacerbate the retinal phenotype. There were also two other unaffected individuals (1 het 1 WT/WT). This counts as 1 affected segregation and 2 unaffected segs
PubMed:20440071
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
not used for AR
This paper identified the variant in a patient with cochear implants but there was no further genotyping or phenotyping information. It is therefore unclear as to whether the patient was heterozygous or compound heterozygous. Though this piece of evidence cannot be used for Usher syndrome in this gene as it Is recessive, it is worth noting this proband information here.
PubMed:20613545
Kimberling last author on this paper as well. Same situation, the deletion causing the frameshift was observed in a family in this study but there is no indication of the phase, just that it is present in an Usher family.
PubMed:10729113
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2018-09-25
Published on: 2019-07-17
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