ClinVar Miner

Submissions for variant NM_004006.2(DMD):c.8983G>A (p.Val2995Ile) (rs148643665)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000541472 SCV000625982 uncertain significance Duchenne muscular dystrophy 2017-04-20 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2995 of the DMD protein (p.Val2995Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs148643665, ExAC 0.02%) but has not been reported in the literature in individuals with a DMD-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786300 SCV000925063 uncertain significance not provided 2017-04-28 no assertion criteria provided provider interpretation p.Val2995Ile (c.8983G>A) in exon 60 of the DMD gene (NM_004006.2) Given the lack of case data and lack of phenotype (HCM)-gene correlation, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). This variant has not been reported in the literature in association with DMD-associated disease. The valine at codon 2995 is conserved across species. However, neighboring amino acids are not. The variant was reported online in 4 of 178,569 chromosomes of individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. One of these individuals was a hemizygote. Specifically, the variant was observed in 3 of 9,571 females of South Asian descent (MAF=0.016%) and 1 out of 79,984 chromosomes of individuals of European descent. This European individual is a male. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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