Submissions for variant NM_000090.4(COL3A1):c.2723C>T (p.Ala908Val)

dbSNP: rs144036995

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000400728	SCV000425533	benign	Ehlers-Danlos syndrome, type 4	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000521444	SCV000620190	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Has not been previously published in association with a connective tissue disorder phenotype to our knowledge; 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); This variant is associated with the following publications: (PMID: 24121792)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000400728	SCV000631648	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-09-07	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 908 of the COL3A1 protein (p.Ala908Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 333063). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000521444	SCV001153226	uncertain significance	not provided	2019-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001176075	SCV001339911	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-02-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 908 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278511	SCV002565627	uncertain significance	Ehlers-Danlos syndrome	2021-11-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001176075	SCV003838076	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-02-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000400728	SCV004833846	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 908 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.
Ambry Genetics	RCV001176075	SCV005032291	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2023-11-13	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.
PreventionGenetics, part of Exact Sciences	RCV004735482	SCV005351245	likely benign	COL3A1-related disorder	2024-08-22	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).