Submissions for variant NM_000090.4(COL3A1):c.4205C>T (p.Ala1402Val)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002302615	SCV002599083	uncertain significance	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.4205C>T (p.Ala1402Val) results in a non-conservative amino acid change located in the C-terminal domain (IPR000885) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251368 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4205C>T in individuals affected with Ehlers-Danlos Syndrome, Vascular Type and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003098032	SCV003308778	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-02-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1402 of the COL3A1 protein (p.Ala1402Val). 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. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.