Submissions for variant NM_153676.4(USH1C):c.2441C>A (p.Thr814Asn)

gnomAD frequency: 0.00006  dbSNP: rs397517877

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000041278	SCV000064969	uncertain significance	not specified	2017-10-24	criteria provided, single submitter	clinical testing	The p.Thr814Asn variant in USH1C has been previously reported by our laboratory in the heterozygous state in two individuals with hearing loss, including one wi th an alternate etiology. In addition, this variant has been identified in 0.018 % (23/126690) European chromosomes by the Genome Aggregation Database (gnomAD, h ttp://gnomad.broadinstitute.org; dbSNP rs397517877). Although this variant has b een seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr814Asn variant is uncertain. ACMG/AMP Crit eria applied: BP5 (Richards 2015).
Illumina Laboratory Services, Illumina	RCV000397022	SCV000369468	uncertain significance	Usher syndrome type 1C	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000669750	SCV000794532	uncertain significance	Usher syndrome type 1C; Autosomal recessive nonsyndromic hearing loss 18A	2017-09-28	criteria provided, single submitter	clinical testing
GeneDx	RCV002274904	SCV002562271	uncertain significance	not provided	2022-08-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV002274904	SCV003277704	uncertain significance	not provided	2022-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 514 of the USH1C protein (p.Thr514Asn). This variant is present in population databases (rs397517877, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with USH1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 48002). 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. 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.
Natera, Inc.	RCV000397022	SCV002081284	uncertain significance	Usher syndrome type 1C	2020-03-03	no assertion criteria provided	clinical testing