Submissions for variant NM_015404.4(WHRN):c.955G>T (p.Gly319Trp)

dbSNP: rs143165834

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155082	SCV000204766	uncertain significance	not specified	2018-05-25	criteria provided, single submitter	clinical testing	The p.Gly319Trp variant in DFNB31 has been previously reported in the heterozygo us state in one individual with hearing loss by our laboratory and in one indivi dual with Usher syndrome who had two variants in MYO7A that were the likely etio logy of their Usher syndrome (Bujakowska 2014). This variant has been identified in 0.05% (18/34420) of Latino chromosomes by the Genome Aggregation Database (g nomAD, http://gnomad.broadinstitute.org; dbSNP rs143165834). Although this varia nt has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation anal ysis suggest that the p.Gly319Trp variant may impact the protein, though this in formation is not predictive enough to determine pathogenicity. In summary, the c linical significance of the p.Gly319Trp variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3.
Illumina Laboratory Services, Illumina	RCV000277600	SCV000476794	uncertain significance	Autosomal recessive nonsyndromic hearing loss 31	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.
Illumina Laboratory Services, Illumina	RCV000332679	SCV000476795	uncertain significance	Usher syndrome type 2D	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361851	SCV001557841	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 319 of the WHRN protein (p.Gly319Trp). This variant is present in population databases (rs143165834, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with WHRN-related conditions. ClinVar contains an entry for this variant (Variation ID: 178338). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.