ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.4067A>G (p.Asp1356Gly) (rs140952583)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000196787 SCV000249988 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing The D1356G variant of uncertain significance in the COL5A2 gene has not been published as pathogenic or benign to our knowledge. The D1356G variant is observed in 28/34,410 (0.08%) alleles from individuals of Latino background and 69/126,486 (0.05%) alleles from individuals of European (non-Finnish) background in large population cohorts (Lek et al., 2016). In addition, although D1356G has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for connective tissue disorder testing at GeneDx, limited segregation data from two relatives with signs/symptoms of EDS suggests lack of variant segregation with disease in the family. Furthermore, D1356G is not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014). Nevertheless, D1356G 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. Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Illumina Clinical Services Laboratory,Illumina RCV000299510 SCV000425614 likely benign Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000472827 SCV000547866 uncertain significance Ehlers-Danlos syndrome, classic type 2018-06-25 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1356 of the COL5A2 protein (p.Asp1356Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs140952583, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213125). 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"; Align-GVGD: "Class C0"). 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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