Submissions for variant NM_005219.5(DIAPH1):c.2333A>G (p.Gln778Arg)

dbSNP: rs369255077

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000388207	SCV000453367	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000602949	SCV000711016	uncertain significance	not specified	2017-02-16	criteria provided, single submitter	clinical testing	The p.Gln778Arg variant in DIAPH1 has not been previously reported in individual s with hearing loss, but has been reported in ClinVar (Variation ID# 351286) as a variant of uncertain significance. This variant has also been identified in 4/ 64508 of European chromosomes by the Exome Aggregation Consortium (ExAC, http:// exac.broadinstitute.org; dbSNPrs369255077). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathog enic role. Computational prediction tools and conservation analysis do not provi de strong support for or against an impact to the protein. In summary, the clini cal significance of the p.Arg118Trp variant is uncertain.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001219655	SCV001391605	uncertain significance	Autosomal dominant nonsyndromic hearing loss 1; Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 778 of the DIAPH1 protein (p.Gln778Arg). This variant is present in population databases (rs369255077, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with DIAPH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 351286). 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 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.
Ambry Genetics	RCV002520325	SCV003531635	uncertain significance	Inborn genetic diseases	2021-07-26	criteria provided, single submitter	clinical testing	The c.2333A>G (p.Q778R) alteration is located in exon 16 (coding exon 16) of the DIAPH1 gene. This alteration results from a A to G substitution at nucleotide position 2333, causing the glutamine (Q) at amino acid position 778 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.