ClinVar Miner

Submissions for variant NM_153676.4(USH1C):c.307C>T (p.Arg103Cys) (rs397517880)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000041289 SCV000064980 uncertain significance not specified 2014-09-04 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Arg103Cys v ariant in USH1C has been reported in one French individual with Usher syndrome t ype I (Besnard 2014) and has been identified in one Indian individual with senso rineural hearing loss by our laboratory (LMM unpublished data); however a second variant in USH1C was not detected in either individual. This variant is absent from large population studies. Another amino acid change at this position (Arg10 3His) has been identified in two individuals with Usher syndrome who were compou nd heterozygous with another pathogenic USH1C (Roux 2006, Saihan 2011), and the variant segregated with disease in an affected sibling of one of those individua ls (Saihain 2011). These data suggest that variants that alter the arginine resi due at position 103 may not be tolerated. Computational prediction tools and con servation analyses suggest that the Arg103Cys variant may impact the protein, th ough this information is not predictive enough to determine pathogenicity. In su mmary, while there is some suspicion for a pathogenic role, the clinical signifi cance of the Arg103Cys variant is uncertain.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756870 SCV000884833 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing The USH1C c.307C>T; p.Arg103Cys variant (rs397517880) has been reported in the heterozygous state in a single individual diagnosed with Usher Syndrome type I (Besnard 2014). Another variant affecting this codon, Arg103His, has also been reported in two individuals with Usher Syndrome (Roux 2006, Saihan 2011). However, this variant is listed in the genome Aggregation Database (gnomAD) with a South Asian population frequency of 0.8% (identified on 261 out of 30,776 chromosomes, including 3 homozygotes) and is classified as a variant of uncertain significance in ClinVar (ID: 48013). The arginine at position 103 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg103Cys variant on protein structure and function predict a deleterious effect (SIFT: damaging, PolyPhen-2: probably damaging). Based on the available information, the clinical significance of the p.Arg103Cys variant cannot be determined with certainty.
Invitae RCV000756870 SCV001034686 benign not provided 2020-12-04 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000756870 SCV001146585 likely benign not provided 2019-07-15 criteria provided, single submitter clinical testing

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