Submissions for variant NM_015404.4(WHRN):c.1349G>A (p.Arg450His)

gnomAD frequency: 0.00007  dbSNP: rs200377723

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038866	SCV000062544	uncertain significance	not specified	2015-07-14	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg450His var iant in DFNB31 has been identified by our laboratory in 1 individual with sensor ineural hearing loss but a second DFNB31 variant has not been identified. This v ariant has also been identified in 0.2% (19/8644) of East Asian chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 00377723). Arginine (Arg) at position 450 is not conserved in mammals or evoluti onarily distant species. Of note, horse has a histidine (His) at this position, raising the possibility that this change may be tolerated. Additional computati onal prediction tools do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of the p.Arg450His vari ant is uncertain, its frequency in the general population and conservation data suggest that it is more likely to be benign.
Illumina Laboratory Services, Illumina	RCV001168063	SCV001330621	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 Laboratory Services, Illumina	RCV001168064	SCV001330622	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.
Invitae	RCV001206517	SCV001377828	uncertain significance	not provided	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 450 of the WHRN protein (p.Arg450His). This variant is present in population databases (rs200377723, gnomAD 0.2%). 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: 45648). 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.
GeneDx	RCV001206517	SCV001982166	uncertain significance	not provided	2021-09-01	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