Submissions for variant NM_000090.4(COL3A1):c.3937A>G (p.Lys1313Glu)

dbSNP: rs886038983

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001190200	SCV000738556	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2017-11-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV001190200	SCV001357642	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-25	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1313 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 2/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001860393	SCV002201264	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-07-17	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (Invitae). This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 1313 of the COL3A1 protein (p.Lys1313Glu). This variant is present in population databases (no rsID available, gnomAD 0.002%). ClinVar contains an entry for this variant (Variation ID: 519617). 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. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223885	SCV002502367	uncertain significance	not provided	2021-09-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527684	SCV004105295	uncertain significance	COL3A1-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	The COL3A1 c.3937A>G variant is predicted to result in the amino acid substitution p.Lys1313Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-189875017-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001860393	SCV004825542	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 1313 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240338	SCV005887987	uncertain significance	not specified	2025-01-07	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.3937A>G (p.Lys1313Glu) results in a conservative amino acid change located in the Fibrillar collagens C-terminal domain (IPR000885) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 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.3937A>G in individuals affected with Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 519617). Based on the evidence outlined above, the variant was classified as uncertain significance.