Submissions for variant NM_015404.4(WHRN):c.191C>A (p.Ala64Asp) (rs146655362)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000038882	SCV000062560	likely benign	not specified	2012-12-28	criteria provided, single submitter	clinical testing	Ala64Asp in exon 1 of DFNB31: This variant is not expected to have clinical sign ificance because it has been identified in 0.2% (15/8598) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs146655362).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000723700	SCV000113670	uncertain significance	not provided	2013-08-16	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000291435	SCV000476806	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.
Illumina Clinical Services Laboratory,Illumina	RCV000346369	SCV000476807	uncertain significance	Deafness, autosomal recessive 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.
Invitae	RCV000723700	SCV001208506	uncertain significance	not provided	2019-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with aspartic acid at codon 64 of the WHRN protein (p.Ala64Asp). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is present in population databases (rs146655362, ExAC 0.1%). This variant has not been reported in the literature in individuals with WHRN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Division of Human Genetics,Children's Hospital of Philadelphia	RCV000477861	SCV000536781	uncertain significance	Deafness, autosomal recessive 31; Usher syndrome, type 2D	2015-10-13	no assertion criteria provided	research