The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
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Variant: NM_206933.4(USH2A):c.6730G>A (p.Val2244Met)

CA179542

166479 (ClinVar)

Gene: USH2A
Condition: Usher syndrome
Inheritance Mode: Autosomal recessive inheritance
UUID: 0b9c3253-8942-49de-9ca6-211abc93baa0
Approved on: 2024-06-28
Published on: 2024-06-28

HGVS expressions

NM_206933.4:c.6730G>A
NM_206933.4(USH2A):c.6730G>A (p.Val2244Met)
NC_000001.11:g.215993095C>T
CM000663.2:g.215993095C>T
NC_000001.10:g.216166437C>T
CM000663.1:g.216166437C>T
NC_000001.9:g.214233060C>T
NG_009497.1:g.435302G>A
NG_009497.2:g.435354G>A
ENST00000307340.8:c.6730G>A
ENST00000674083.1:c.6730G>A
ENST00000307340.7:c.6730G>A
NM_206933.2:c.6730G>A
NM_206933.3:c.6730G>A
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Uncertain Significance

Met criteria codes 3
PP4 PM3_Supporting BS1
Not Met criteria codes 2
PP3 BP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Hearing Loss Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDH23, COCH, GJB2, KCNQ4, MYO6, MYO7A, SLC26A4, TECTA and USH2A Version 2

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Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Hearing Loss VCEP
The c.6730G>A (p.Val2244Met) variant in USH2A is a missense variant predicted to cause a substitution of valine by methionine at amino acid 2244. The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1. The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID: 27460420) (PM3_Supporting). At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID: 27460420). In summary, this variant meets the criteria to be classified as uncertain significance for autosomal recessive Usher syndrome, based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP (BS1, PM3_Supporting, PP4; Version 2; 5/15/24).
Met criteria codes
PP4
At least one patient with this variant displayed retinitis pigmentosa and sensorineural bilateral hearing loss, which is highly specific for Usher syndrome (PP4; PMID: 27460420).
PM3_Supporting
This variant has been detected in at least one individual with Usher syndrome. This individual was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (p.Leu4567Profs*16; PMID: 27460420) (PM3_Supporting).
BS1
The filtering allele frequency (the lower threshold of the 95% CI of 312/91082) of the c.6730G>A (p.Val2244Met) is 0.3112% for South Asian chromosomes by gnomAD v4.1.0, which meets the ClinGen Hearing Loss VCEP threshold (≥0.003) for BS1.
Not Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function.
BP4
The computational predictor REVEL gives a score of 0.28, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function.
Curation History
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