ClinVar Miner

Submissions for variant NM_153676.4(USH1C):c.1858C>T (p.Arg620Cys) (rs143160805)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000835046 SCV000976824 likely benign not provided 2018-05-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000835046 SCV001148195 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001002461 SCV001160404 uncertain significance not specified 2019-04-09 criteria provided, single submitter clinical testing The USH1C c.1858C>T; p.Arg620Cys variant (rs143160805) is reported in the literature in two siblings affected with nonsyndromic hearing loss (Ganapathy 2014). This variant is found in the South Asian population with an overall allele frequency of 0.33% (102/30490 alleles, including three homozygotes) in the Genome Aggregation Database. The arginine at codon 620 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg620Cys variant is uncertain at this time. References: Ganapathy A et al. Non-syndromic hearing impairment in India: high allelic heterogeneity among mutations in TMPRSS3, TMC1, USHIC, CDH23 and TMIE. PLoS One. 2014 Jan 8;9(1):e84773.
Invitae RCV000835046 SCV001733242 benign not provided 2020-12-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001002461 SCV001552816 benign not specified no assertion criteria provided clinical testing The USH1C p.Arg620Cys variant was identified in a compound heterozygote individual with autosomal recessive non-syndromic hearing loss (Ganapathy_2014_PMID:24416283). The variant was identified in dbSNP (ID: rs143160805), ClinVar (classified as likely benign by GeneDx), and LOVD 3.0. The variant was identified in control databases in 150 of 281130 chromosomes (3 homozygous) at a frequency of 0.0005336 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 102 of 30490 chromosomes (freq: 0.003345), Other in 3 of 7178 chromosomes (freq: 0.000418), Latino in 11 of 35364 chromosomes (freq: 0.000311), European (non-Finnish) in 32 of 128200 chromosomes (freq: 0.00025) and East Asian in 2 of 19938 chromosomes (freq: 0.0001), but was not observed in the African, Ashkenazi Jewish, or European (Finnish) populations. The p.Arg620 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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