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]

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Variant: NM_206933.4(USH2A):c.6233C>G (p.Pro2078Arg)

CA179550

166488 (ClinVar)

Gene: USH2A

Condition: Usher syndrome

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: 57f01c09-b6e9-4a7f-8b94-9efd6e2f985c

Approved on: 2020-06-24

Published on: 2020-06-26

HGVS expressions

NM_206933.4:c.6233C>G

NM_206933.4(USH2A):c.6233C>G (p.Pro2078Arg)

NM_206933.2:c.6233C>G

NM_206933.3:c.6233C>G

ENST00000307340.7:c.6233C>G

NC_000001.11:g.216046523G>C

CM000663.2:g.216046523G>C

NC_000001.10:g.216219865G>C

CM000663.1:g.216219865G>C

NC_000001.9:g.214286488G>C

NG_009497.1:g.381874C>G

NG_009497.2:g.381926C>G

Uncertain Significance

BS1_Supporting PP3 PM3_Supporting

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 c.6233C>G (p.Pro2078Arg) variant in USH2A was present in 0.39% (lower bound of the 95% CI of 50/10070) of Ashkenazi Jewish alleles in gnomAD v3. Although this population frequency is high enough to meet BS1, this evidence was downgraded to BS1_Supporting because this variant is likely a founder mutation in the Ashkenazi Jewish population. The p.Pro2078Arg variant was observed in one proband with retinitis pigmentosa and a second pathogenic variant in USH2A (PM3_Supporting; Hadassah-Hebrew University Medical Center internal data, ClinVar SCV001161352.1). It has also been seen in at least 4 probands without a second variant identified in USH2A (Laboratory for Molecular Medicine and Invitae internal data, ClinVar SCV000201902.5, SCV001068267.2). The REVEL computational prediction tool produced a score of 0.702, which is above the threshold necessary to apply PP3. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BS1_Supporting, PM3_Supporting, PP3.

BS1_Supporting

Present in 0.4965% (50/10070, 95% CI 0.39%) of Ashkenazi Jewish alleles in gnomAD v2. However, the next highest population frequencies (aside from in the "other" group in gnomAD) were 0.006% (7/113522) and 0.005% (3/64534) of non-Finnish European alleles in gnomAD v2 and v3, respectively. Because this variant is likely a founder population in the AJ population, BS1 was downgraded to BS1_Supporting.

PP3

REVEL 0.702. Entirely conserved in UCSC database. Not predicted to impact splicing.

PM3_Supporting

Seen in 1 patient with RP, compound het. with c.12067-2A>G, a founder mutation that causes loss of the canonical splice acceptor site in intron 61. Phase was not determined.

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