ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.1621G>T (p.Ala541Ser) (rs768348357)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617633 SCV000738707 uncertain significance Cardiovascular phenotype 2016-03-30 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 RCV000196281 SCV000249959 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing The A541S variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The A541S 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 A541S 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. This substitution occurs at a position that is conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating this region of the protein may be tolerant of change. Finally, although the A541S variant is located in the triple helical region of COL5A2, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of missense mutations occur (Stenson et al., 2014; Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
GenomeConnect, ClinGen RCV000705651 SCV000986743 not provided Ehlers-Danlos syndrome, classic type no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 11/10/2015 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000705651 SCV000834659 uncertain significance Ehlers-Danlos syndrome, classic type 2018-06-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 541 of the COL5A2 protein (p.Ala541Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs768348357, ExAC 0.005%). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213098). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). 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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