ClinVar Miner

Submissions for variant NM_206933.4(USH2A):c.13396C>T (p.Pro4466Ser) (rs138398671)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Hearing Loss Variant Curation Expert Panel RCV001004775 SCV001164257 uncertain significance Usher syndrome 2019-03-25 reviewed by expert panel curation The p.Pro4466Ser variant in USH2A has been identified in one European patient with retinitis pigmentosa who also carried another rare "unspecified" USH2A variant. No phase or inheritance information was provided for either variant (PMID: 28041643). The allele frequency of the p.Pro4466Ser variant in the USH2A gene is 0.004% (57/128,120) of non-Finnish European chromosomes by gnomAD, which is a low enough frequency to apply PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2_Supporting). Computational prediction analysis using the metapredictor tool REVEL suggests that the variant may not impact the protein (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, BP4.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041740 SCV000065436 likely benign not specified 2012-05-07 criteria provided, single submitter clinical testing Pro4466Ser in exon 63 of USH2A: This variant has been identified in 0.04% (3/702 0) of European American chromosomes in a broad population by the NHLBI Exome seq uencing project (; dbSNP rs138398671). This var iant is not expected to have clinical significance due to a lack of conservation of the amino acid position. Of note, chicken has a serine (Ser) at this positio n despite high nearby amino acid conservation.
Counsyl RCV000672135 SCV000797202 uncertain significance Usher syndrome, type 2A; Retinitis pigmentosa 39 2018-03-30 criteria provided, single submitter clinical testing
Invitae RCV001035021 SCV001198326 uncertain significance not provided 2019-12-02 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 4466 of the USH2A protein (p.Pro4466Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs138398671, ExAC 0.05%). This variant has been observed in an individual affected with retinitis pigmentosa (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 48417). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000505044 SCV000598788 likely pathogenic Retinitis pigmentosa 2015-01-01 no assertion criteria provided research

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