ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.4307C>T (p.Pro1436Leu) (rs752334702)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198189 SCV000249834 uncertain significance not provided 2019-01-14 criteria provided, single submitter clinical testing The P1436L variant of uncertain significance in the COL5A1 gene has not been published as pathogenic or benign to our knowledge. This variant has been identified both independently and in conjunction with additional cardiogenetic variants in individuals referred for genetic testing at GeneDx; thus far, segregation data is limited for these individuals. The P1436L variant is observed in 9/271740 (0.003%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). Although this variant is located in the triple helical region of COL5A1, it does not affect a glycine residue in a Gly-X-Y motif within this region, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Nevertheless, the P1436L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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.
Invitae RCV000230482 SCV000283494 uncertain significance Ehlers-Danlos syndrome, classic type 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1436 of the COL5A1 protein (p.Pro1436Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs752334702, ExAC 0.007%). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212977). 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.
Ambry Genetics RCV000619006 SCV000738682 uncertain significance Cardiovascular phenotype 2019-10-18 criteria provided, single submitter clinical testing Insufficient evidence
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659461 SCV000781276 uncertain significance Connective tissue disease 2016-11-01 criteria provided, single submitter clinical testing

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