ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.1303C>G (p.Pro435Ala) (rs377488010)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198331 SCV000249880 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing The P435A variant in the COL5A1 gene has been observed in one individual with a clinical diagnosis of Ehlers-Danlos syndrome as reported in an abstract for the American Society of Human Genetics Annual Meeting (Dupuis, L., 2012). In addition, the P435A variant has been identified in one other individual who had DNA-based testing for TAAD at GeneDx. Furthermore, the P435A variant was not observed with any significant frequency 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 P435A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species; however, it does not affect a Glycine residue in the Gly-X-Y motif in the triple helical regions of the COL5A1 gene, 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. Finally, no missense variants in nearby residues have been reported in the Human Gene Mutation Database (Stenson et al., 2014), indicating that this region of the gene is not known to harbor disease-causing variants.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000617572 SCV000738624 uncertain significance Cardiovascular phenotype 2019-04-15 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000509171 SCV000755971 uncertain significance Ehlers-Danlos syndrome, classic type 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 435 of the COL5A1 protein (p.Pro435Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs377488010, ExAC 0.005%). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 213021). 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: "Probably Damaging"; 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000852013 SCV000899471 uncertain significance Abnormal bleeding 2019-02-01 criteria provided, single submitter research
GenomeConnect, ClinGen RCV000509171 SCV000606939 not provided Ehlers-Danlos syndrome, classic type no assertion provided phenotyping only 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.

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