ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.2993A>T (p.Gln998Leu)

dbSNP: rs139859476
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000788269 SCV000927321 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing
GeneDx RCV000788269 SCV004021727 uncertain significance not provided 2023-01-23 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD)
Labcorp Genetics (formerly Invitae), Labcorp RCV003633547 SCV004524192 uncertain significance Ehlers-Danlos syndrome, type 4 2023-11-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 998 of the COL3A1 protein (p.Gln998Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 636439). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function with a negative predictive value of 95%. 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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