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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Variant: NM_206933.2(USH2A):c.1036A>C (p.Asn346His)
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CA262054
48347 (ClinVar)
Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 211c3a9c-3789-42d9-ab55-04892c95f534
Approved on: 2018-09-14
Published on: 2019-07-17
HGVS expressions
NM_206933.2:c.1036A>C
NM_206933.2(USH2A):c.1036A>C (p.Asn346His)
NC_000001.11:g.216325412T>G
CM000663.2:g.216325412T>G
NC_000001.10:g.216498754T>G
CM000663.1:g.216498754T>G
NC_000001.9:g.214565377T>G
NG_009497.1:g.102985A>C
NM_007123.5:c.1036A>C
NM_206933.3:c.1036A>C
ENST00000307340.7:c.1036A>C
ENST00000366942.3:c.1036A>C
More
Pathogenic
Met criteria codes 5
PP1_Strong
PM3_Very Strong
PP4
PP3
PM2_Supporting
Not Met criteria codes 18
PVS1
BA1
BS2
BS1
BS4
BP5
BP7
BP2
BP4
BP3
PS4
PS2
PS1
PS3
PM6
PM5
PM1
PM4
Evidence Links 7
Expert Panel
Evidence submitted by expert panel
Hearing Loss VCEP
The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). 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_Supporting, PP1_S, PM3_VS, PP4, PP3.
Met criteria codes
PP1_Strong
Cosegretation with the phenotype were observed in at least 7 families including 13 affected members.
Agree with this code usage. MD
The Asn346His variant was identified in 1 proband in combination with a second loss of function allele c.1227G>A (p.Trp409X)
PubMed:15241801
1 compound het proband with Arg1295X on remaining allele. Variants segregated in 3 affected relatives. 1 homozygous proband, variant segregated in 2 affected relatives.
PubMed:24160897
The Asn346His variant was identified in 2 probands with USH2. It was observed in a large Swedish family with Arg1295X, but the two variants were not present in the same individuals. In an American family, it was compound heterozygous with another pathogenic variant 2299delG (Glu767fs). The cDNA coordinate (c.1042A>C = p.348) in this paper was wrong, but the alignment figure showed the variant matching N346H.
PubMed:10729113
Asn346His variant was identified in 1 proband with USH2, compound heterozygous with Gly4403fs variant
PubMed:17405132
Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe. One individual was het only.
PubMed:22135276
Two siblings were cmp het for this variant and Thr4439Ile. The brother had Usher syndrome. The 43 year old sister had hearing loss and a slightly abnormal finding on ERG, but was otherwise normal.
PubMed:25521520
PM3_Very Strong
This could actually be upgraded to PM3_very strong. There are >4 cases of this variant being identified in trans with a known pathogenic variant. I've added more publications below.
-MD
detected in trans with p.Trp409X
PubMed:15241801
detected in trans with p.R1295X
PubMed:24160897
detected in trans with c.2299del
PubMed:26969326
detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe
PubMed:22135276
PP4
The patiens of compound heterozygotes or homozygotes with the mutation showed retinitis pigmentosa with hearing loss.
Enough patients were also tested for the other Usher syndrome genes and found to be negative for changes in them. I also agree.
-MD
The Asn346His variant was identified in 1 proband in combination with a second loss of function allele c.1227G>A (p.Trp409X).
PubMed:15241801
1 compound het proband with Arg1295X on remaining allele. Variants segregated in 3 affected relatives. 1 homozygous proband, variant segregated in 2 affected relatives.
PubMed:24160897
Asn346His variant was identified in 1 proband with USH2, compound heterozygous with Gly4403fs variant
PubMed:17405132
The Asn346His variant was identified in 2 probands with USH2. It was observed in a large Swedish family with Arg1295X, but the two variants were not present in the same individuals. In an American family, it was compound heterozygous with another pathogenic variant 2299delG (Glu767fs). The cDNA coordinate (c.1042A>C = p.348) in this paper was wrong, but the alignment figure showed the variant matching N346H.
PubMed:10729113
Usher syndrome type II
PubMed:22135276
Two siblings were cmp het for this variant and Thr4439Ile. The brother had Usher syndrome. The 43 year old sister had hearing loss and a slightly abnormal finding on ERG, but was otherwise normal.
PubMed:25521520
PP3
Agree. REVEL is >0.7
-MD
PM2_Supporting
I agree. Variant is present in (20/126318) ) 0.00015% Europeans in gnomAD.
-MD
Not Met criteria codes
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
I agree. Variant is present in (20/126318) ) 0.00015% Europeans in gnomAD.
-MD
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
I agree. Variant is present in (20/126318) ) 0.00015% Europeans in gnomAD.
-MD
BS4
The Asn346His variant was identified in 1 proband in combination with a second loss of function allele c.1227G>A (p.Trp409X)
PubMed:15241801
1 compound het proband with Arg1295X on remaining allele. Variants segregated in 3 affected relatives. 1 homozygous proband, variant segregated in 2 affected relatives.
PubMed:24160897
The Asn346His variant was identified in 2 probands with USH2. It was observed in a large Swedish family with Arg1295X, but the two variants were not present in the same individuals. In an American family, it was compound heterozygous with another pathogenic variant 2299delG (Glu767fs). The cDNA coordinate (c.1042A>C = p.348) in this paper was wrong, but the alignment figure showed the variant matching N346H.
PubMed:10729113
Asn346His variant was identified in 1 proband with USH2, compound heterozygous with Gly4403fs variant
PubMed:17405132
Four compound hets reported; variants on remaining allele were Thr4439Ile, Glu3305fs, Trp3521Arg, Cys419Phe. One individual was het only.
PubMed:22135276
Two siblings were cmp het for this variant and Thr4439Ile. The brother had Usher syndrome. The 43 year old sister had hearing loss and a slightly abnormal finding on ERG, but was otherwise normal.
PubMed:25521520
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
detected in trans with p.Trp409X
PubMed:15241801
detected in trans with p.R1295X
PubMed:24160897
detected in trans with c.2299del
PubMed:26969326
detected in trans with p.Glu3305ArgfsX41, p.Trp3521Arg, and Lys419Phe
PubMed:22135276
BP4
Agree. REVEL is >0.7
-MD
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
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
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
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
PM1
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
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