ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.3038C>T (p.Ala1013Val) (rs372220538)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000699351 SCV000828057 uncertain significance Ehlers-Danlos syndrome, classic type 2019-10-26 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1013 of the COL5A2 protein (p.Ala1013Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs372220538, ExAC 0.07%). This variant has not been reported in the literature in individuals with COL5A2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C55"). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000755981 SCV000883670 uncertain significance not provided 2017-11-13 criteria provided, single submitter clinical testing One variant of uncertain clinical significance, c.3038C>T; p.Ala1013Val, was detected in the COL5A2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The p.Ala1013Val (rs372220538) is listed in the Exome Aggregation Consortium Browser with an overall allele frequency of 0.01 percent (identified in 2 out of 20,648 chromosomes) and with frequency of 0.07 percent (identified in 2 out of 2726 chromosomes) in African populations. This variant has not been previously reported in the scientific literature or gene-specific variant databases. We have previously identified this variant in an individual with subtle skeletal findings who also carried pathogenic variant in the SMAD3 gene. The alanine 1013 is highly conserved up to Xenopus tropicalis but computational prediction programs do not agree in assessing the effect of this variant (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: disease causing). p.Ala1013Val is not located in the triple helix domain and computational splice prediction programs do not suggest significant effect on splicing (Alamut software v.2.7.1).. Altogether, there is not enough information to classify this variant with certainty. Pathogenic COL5A2 variants are associated with Ehlers-Danlos syndrome, type I (MIM:130000).

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