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

gnomAD frequency: 0.00030  dbSNP: rs143160805

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000835046	SCV000976824	benign	not provided	2020-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24416283, 30245029, 26186295)
CeGaT Center for Human Genetics 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	2023-09-21	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.