Submissions for variant NM_004006.3(DMD):c.4296G>C (p.Gln1432His)

dbSNP: rs747262903

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630524	SCV000751486	uncertain significance	Duchenne muscular dystrophy	2021-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1432 of the DMD protein (p.Gln1432His). This variant is present in population databases (no rsID available, gnomAD 0.008%). This missense change has been observed in individual(s) with duchenne muscular dystrophy (PMID: 27263301). This variant is also known as p.Gln1424His. ClinVar contains an entry for this variant (Variation ID: 526068). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264502	SCV001442687	uncertain significance	not specified	2020-10-12	criteria provided, single submitter	clinical testing	Variant summary: DMD c.4296G>C (p.Gln1432His) results in a non-conservative amino acid change located in the Central rod domain: Repeat 10 (DOVE) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-06 in 182711 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4296G>C has been reported in the literature in one individual affected with Duchenne muscular dystrophy (Wang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002331108	SCV002629587	uncertain significance	Cardiovascular phenotype	2021-04-06	criteria provided, single submitter	clinical testing	The p.Q1432H variant (also known as c.4296G>C), located in coding exon 31 of the DMD gene, results from a G to C substitution at nucleotide position 4296. The glutamine at codon 1432 is replaced by histidine, an amino acid with highly similar properties. Based on data from gnomAD, the C allele has an overall frequency of 0.0005%% (1/182711) total alleles studied, with no hemizygotes observed. The highest observed frequency was 0.007% (1/13786) of East Asian alleles. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Natera, Inc.	RCV001834992	SCV002085338	uncertain significance	Becker muscular dystrophy; Duchenne muscular dystrophy; Cardiomyopathy; Dystrophin deficiency	2019-08-26	no assertion criteria provided	clinical testing