Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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  • See Evidence submitted by expert panel for details.

Variant: NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs)

CA273289

166504 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 34c5d011-929d-4998-ae9a-ef900674144e
Approved on: 2018-09-10
Published on: 2019-07-17

HGVS expressions

NM_206933.2:c.4510_4511insA
NM_206933.2:c.4510dupA
NM_206933.2(USH2A):c.4510dupA (p.Arg1504Lysfs)
NM_007123.5:c.4510dup
NM_206933.2:c.4510dup
NM_206933.3:c.4510dup
ENST00000307340.7:c.4510dup
ENST00000366942.3:c.4510dup
NC_000001.11:g.216175371dup
CM000663.2:g.216175371dup
NC_000001.10:g.216348713dup
CM000663.1:g.216348713dup
NC_000001.9:g.214415336dup
NG_009497.1:g.253028dup

Pathogenic

Met criteria codes 4
PVS1 PP4 PM2 PM3_Strong
Not Met criteria codes 19
PS1 PS4 PS3 PS2 BP4 BP3 BP2 BP7 BP5 BA1 PP3 PP1 PM6 PM5 PM4 PM1 BS2 BS1 BS4

Evidence Links 4

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.4510dupA (p.Arg1504LysX26) variant in USH2A is predicted to cause a premature stop codon in biologically-relevant-exon 21/72 that leads to a truncated or absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected in 2 patients with hearing loss in trans with 2 different pathogenic variants (PM3_S; PMID:22135276). The allele frequency of the p.Arg1504LysX26 variant in the USH2A gene is 0.003% (3/111138) of European 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). At least one patient with a variant in this gene displayed features of retinitis pigmentosa (PP4; PMID: 22135276). 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: PVS1, PM3_S, PM2, PP4.
Met criteria codes
PVS1
Variant is in a gene with established LOF mech. It is expected to cause a frameshift resulting in a stop codon 26 amino acids away resulting in a truncated protein. There is only one other LOF variant in gnomAD in this exon and there are only 8 alleles suggesting that LOF in this exon is restricted. RS: This variant occurs in the last exon of the shorter transcript, however the shorter transcript is not biologically relevant.
PP4
Patients with RP and Usher syndrome type 2 were identified to have this variant as well as another path variant in trans.
PM2
3/111138 European alleles 0.00002699 < 0.00007, meets PM2 cutoff which is now PM2_Supporting RS: Under current guidelines, this meets PMS_Moderate.
PM3_Strong
There were 2 occasions where this variant was observed in trans with another LOF variant and another instance where the variant was identified in trans with the p.Cys419Phe variant which is Path/LP in ClinVar by 6 submitters.
Total: 3 Path variants in trans. The variant was detected in a proband from a UK study with Usher type 2 in trans with the p.Trp2744X variant. The variant was also identified in two more USH2A patients, one with a p.Cys419Phe which is a P/LP variant and another in a proband with the p.Glu767SerfsX21 variant. Patients were recruited through Moorfields Eye Hospital which was also the case of the patient described in Carss 2017, though that proband was not counted because the other allele was not identified. PubMed:22135276
Not Met criteria codes
PS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This is not used as a proband count for autosomal recessive though a statistical analysis could be done. There were no statistical analyses including his variant.
This paper used WGS to identify the variant in a patient with RP. The patient was not diagnosed with Usher Syndrome, and the zygosity was not reported. Therefore, this cannot be counted in the PM3 evidence. PubMed:28041643
This study identified the variant in a patient with Usher 2, but did nto identify any variant in trans. The same is true for Weston 2000, which is the same group, and likely the same patient. PubMed:15325563
This study identified the variant in a patient with Usher 2, but did nto identify any variant in trans. The same is true for Seyedahmadi 2004, which is the same group, and likely the same patient. PubMed:10729113
PS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2
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
Total: 3 Path variants in trans. The variant was detected in a proband from a UK study with Usher type 2 in trans with the p.Trp2744X variant. The variant was also identified in two more USH2A patients, one with a p.Cys419Phe which is a P/LP variant and another in a proband with the p.Glu767SerfsX21 variant. Patients were recruited through Moorfields Eye Hospital which was also the case of the patient described in Carss 2017, though that proband was not counted because the other allele was not identified. PubMed:22135276
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
BA1
3/111138 European alleles 0.00002699 < 0.00007, meets PM2 cutoff which is now PM2_Supporting RS: Under current guidelines, this meets PMS_Moderate.
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP1
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
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
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
3/111138 European alleles 0.00002699 < 0.00007, meets PM2 cutoff which is now PM2_Supporting RS: Under current guidelines, this meets PMS_Moderate.
BS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
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