Submissions for variant NM_015404.4(WHRN):c.2354C>T (p.Thr785Ile)

gnomAD frequency: 0.00019  dbSNP: rs201555289

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038891	SCV000062569	uncertain significance	not specified	2012-12-20	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Thr785Ile varia nt in DFNB31 has not been reported in the literature nor previously identified b y our laboratory. Computational analyses (biochemical amino acid properties, con servation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Thr785Ile variant ma y not impact the protein. In addition, this variant has been identified in 0.03% (3/8600) of European American chromosomes and 0.02% (1/4406) of African America n chromosomes in a broad population by the NHLBI Exome sequencing project (http: //evs.gs.washington.edu/EVS/; dbSNP rs201555289). In summary, computational ana lyses predictions, lack of conservation at this position, and the presence of th is variant in the general population support a more likely benign role, however additional data is needed to determine its clinical significance with certainty.
Illumina Laboratory Services, Illumina	RCV001169715	SCV001332479	uncertain significance	Autosomal recessive nonsyndromic hearing loss 31	2018-01-13	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	RCV001169716	SCV001332480	uncertain significance	Usher syndrome type 2D	2018-01-13	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	RCV001204993	SCV001376227	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 785 of the WHRN protein (p.Thr785Ile). This variant is present in population databases (rs201555289, gnomAD 0.08%). 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: 45673). 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.
GeneDx	RCV001204993	SCV001875062	likely benign	not provided	2021-09-13	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
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004814959	SCV005073162	uncertain significance	Retinal dystrophy	2023-01-01	no assertion criteria provided	clinical testing