ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1196G>C (p.Gly399Ala)

dbSNP: rs1060500194
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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460412 SCV000541793 likely pathogenic Ehlers-Danlos syndrome, type 4 2018-09-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 399 of the COL3A1 protein (p.Gly399Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. In summary, this variant is a novel missense change affecting a residue crucial for protein structure and stability. Although additional genetic data will be necessary to further confirm pathogenicity for this variant, glycine substitutions located in COL3A1 TH domains are likely deleterious. For these reasons, this variant has been classified as Likely Pathogenic. Glycine residues within the triple helix (TH) domain are important for fibrillar collagens structure and stability (PMID: 7695699, 8218237, 19344236). In the case of COL3A1 the majority of the missense substitutions at the triple helix domain affect glycine residues (PMID: 24922459, 25758994). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL3A1-related disease.

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