ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.3110C>T (p.Thr1037Met) (rs150487609)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197609 SCV000249811 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing The T1037M variant\t of uncertain significance in the COL5A1 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 21/243,594 (0.009%) alleles globally in large population cohorts (Lek et al., 2016). The T1037M 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. Although the T1037M variant is within the triple helical region of the COL5A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). Moreover, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Finally, T1037M has been identified independently and in conjunction with additional cardiogenetic variants in multiple individuals referred for TAAD genetic testing at GeneDx. So far, segregation data is absent for these individuals due to the lack of clinical information provided and insufficient participation by informative family members. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000618911 SCV000738662 uncertain significance Cardiovascular phenotype 2017-04-03 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000698433 SCV000827095 uncertain significance Ehlers-Danlos syndrome, classic type 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 1037 of the COL5A1 protein (p.Thr1037Met). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs150487609, ExAC 0.08%). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 212955). 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 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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