ClinVar Miner

Submissions for variant NM_004006.3(DMD):c.2539A>G (p.Thr847Ala) (rs138145424)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724731 SCV000227672 uncertain significance not provided 2017-06-13 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000223116 SCV000271655 uncertain significance not specified 2015-04-28 criteria provided, single submitter clinical testing The p.Thr847Ala variant in DMD has not been previously reported in individuals w ith cardiomyopathy, but has been identified in 4/8508 African chromosomes, inclu ding one male, by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs138145424). Computational prediction tools and conservation an alysis suggest that this variant may not impact the protein, though this informa tion is not predictive enough to rule out pathogenicity. In summary, the clinica l significance of the p.Thr847Ala variant is uncertain.
GeneDx RCV000223116 SCV000619814 uncertain significance not specified 2017-08-09 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DMD gene. The T847A variant has not been published as pathogenic or been reported as benign to our knowledge. However, this variant has been classified as a variant of uncertain significance by two other clinical laboratories in ClinVar (SCV000227672.3, SCV000271655.1; Landrum et al., 2016). The T847A variant is observed in 4/8508 (0.05%) alleles from individuals of African ancestry, including one hemizygous individual, in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). This substitution occurs at a position that is only conserved in mammals, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense variants represent the minority of disease-causing variants, with 65-70% of pathogenic variants in the DMD gene being exon-level deletions and duplications (Aartsma-Rus et al., 2006). Nevertheless, the T847A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties.
Ambry Genetics RCV000620846 SCV000737010 uncertain significance Cardiovascular phenotype 2017-01-16 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000685504 SCV000812987 uncertain significance Duchenne muscular dystrophy 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 847 of the DMD protein (p.Thr847Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs138145424, ExAC 0.05%). This variant has not been reported in the literature in individuals with DMD-related disease. ClinVar contains an entry for this variant (Variation ID: 195493). Algorithms developed to predict the effect of missense changes on protein structure and function 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.

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