ClinVar Miner

Submissions for variant NM_004006.2(DMD):c.3028G>C (p.Ala1010Pro) (rs766325631)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766849 SCV000235866 uncertain significance not provided 2014-07-03 criteria provided, single submitter clinical testing p.Ala1010Pro (GCG>CCG): c.3028 G>C in exon 23 of the DMD gene (NM_004006.2). A variant of unknown significance has been identified in the DMD gene. The A1010P variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A1010P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A1010P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function, but overall suggests that this is a damaging variant. Howver, no missense mutations in nearby residues have been reported in association with DMD, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000183409 SCV000280074 uncertain significance not specified 2015-06-16 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the information reviewed below, we classify it as a variant of unknown significance. This variant has not previously been reported as a pathogenic variant in affected individuals, nor as a benign polymorphism according to the GeneDx report and our own Google and database searches. This is a conservative amino acid change, resulting in the replacement of a nonpolar Alanine with a nonpolar Proline. The Alanine at this location is highly conserved across vertebrate species sequenced, although it is instead a Valine in Manatee and a Glycine in two species of bird. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 0.999. No other missense variants within 10 amino acids to either side have been reported in HGMD, indicating that this region of the protein may be tolerant of change. In total the variant has been seen in 1/~42,700 individuals from publicly available population datasets. This variant is not present in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls in DMD on ~1870 Caucasian and ~570 African-American individuals (as of 6/16/2015). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. The variant is not present in dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP). No variation at this codon is present in 1000 Genomes (http://browser.1000genomes.org). It is not present in ClinVar as of 6/16/2015. There is 1 Caucasian individual with this variant in the ExAC dataset, which currently includes variant calls on ~42,700 individuals of multiple ethnic backgrounds (Latino, European (non-Finnish), Finnish, South Asian, African & East Asian). These individuals took part in a range of disease-specific and population genetic studies, and the curators made an effort to exclude individuals with severe pediatric diseases.

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