ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.3418G>A (p.Val1140Met) (rs149616140)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000245297 SCV000320109 uncertain significance Cardiovascular phenotype 2016-04-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000195903 SCV000249907 uncertain significance not specified 2017-03-21 criteria provided, single submitter clinical testing Although the V1140M variant has not been published as a pathogenic variant or as a benign variant to our knowledge, it has been previously identified in other unrelated individuals who underwent genetic testing for Marfan/TAAD. A missense variant in a nearby residue (G1138E) has been reported in the Human Gene Mutation Database in association with EDS (Stenson et al., 2014), supporting the functional importance of this region of the protein. This substitution occurs at a position that is conserved across species. However, the V1140M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, while the V1140M variant occurs within the triple helical region of the COL5A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the NHLBI Exome Sequencing Project and the 1000 Genomes Project report V1140M was observed in approximately 0.1% of alleles from individuals of European and African background. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000548042 SCV000631488 likely benign Ehlers-Danlos syndrome, classic type 2017-12-10 criteria provided, single submitter clinical testing

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