Evidence Repository - Clinical Genome Resources

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

x This classification has been retracted/unpublished!

Variant: NM_206933.3(USH2A):c.12575G>A (p.Arg4192His)

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CA179511

166434 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a38414ae-e328-4518-8105-9299e499fa90

Approved on: 2020-03-19

Published on: 2021-03-30

HGVS expressions

NM_206933.3:c.12575G>A

NM_206933.3(USH2A):c.12575G>A (p.Arg4192His)

NC_000001.11:g.215675336C>T

CM000663.2:g.215675336C>T

NC_000001.10:g.215848678C>T

CM000663.1:g.215848678C>T

NC_000001.9:g.213915301C>T

NG_009497.1:g.753061G>A

NG_009497.2:g.753113G>A

ENST00000307340.7:c.12575G>A

NM_206933.2:c.12575G>A

NM_206933.4:c.12575G>A

Benign

BA1 BP4

Evidence Links 0

Expert Panel

Hearing Loss VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hearing Loss VCEP

The filtering allele frequency (the lower threshold of the 95% CI of 39/3324) of the p.Arg4192His variant in the USH2A gene is 0.882% for Ashkenazi Jewish chromosomes by gnomAD v3, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss variants (BA1). The variant is present in several individuals with retinitis pigmentosa but has not been associated with hearing loss (PM3 not met). Additionally, computational prediction analysis using the metapredictor tool REVEL (0.119) suggests that the variant may not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1, BP4.

BA1

The variant is present in 0.747% (92/10284) (95% CI) of Ashkenazi Jewish chromosomes in gnomAD v2.1.1 and in 0.882% (39/3324) (95% CI) of Ashkenazi Jewish chromosomes in gnomAD v3.

BP4

No splicing impact indicated in Alamut. The REVEL score is 0.119. Prairie vole, platypus, tasmanian devil and few other mammals have a histidine at this position.

Curation History

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