ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.944C>T (p.Thr315Met) (rs145093766)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198620 SCV000249877 uncertain significance not provided 2019-01-15 criteria provided, single submitter clinical testing p.Thr315Met (T315M) ACG>ATG: c.944 C>T in exon 7 of the COL5A1 gene (NM_000093.3) The T315M variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. The T315M variant has been reported in one individual referred for Marfan/TAAD testing at GeneDx. Although the T315M variant was not observed with significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, the 1000 Genomes Project reports T315M was observed in 4/1516 (0.3%) alleles from individuals of African American background. The T315M 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 in mammals. 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 association with EDS, suggesting this region of the protein may be tolerant of change.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1,TAAD
Invitae RCV000554898 SCV000631560 uncertain significance Ehlers-Danlos syndrome, classic type 2019-06-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 315 of the COL5A1 protein (p.Thr315Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs145093766, ExAC 0.05%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with clinical features of Ehlers-Danlos syndrome (PMID: 30858776). ClinVar contains an entry for this variant (Variation ID: 213018). 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: "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.
Ambry Genetics RCV000621289 SCV000738566 uncertain significance Cardiovascular phenotype 2017-02-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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