Submissions for variant NM_000090.4(COL3A1):c.2498A>G (p.Lys833Arg)

gnomAD frequency: 0.00009  dbSNP: rs371344739

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766809	SCV000233334	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463723	SCV000541816	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 833 of the COL3A1 protein (p.Lys833Arg). This variant is present in population databases (rs371344739, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of COL3A1-related disease (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 199701). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000181058	SCV000603137	uncertain significance	not specified	2016-10-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000778018	SCV000738534	benign	Familial thoracic aortic aneurysm and aortic dissection	2022-05-06	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Fulgent Genetics, Fulgent Genetics	RCV000463723	SCV000896915	uncertain significance	Ehlers-Danlos syndrome, type 4	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000778018	SCV000914128	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2024-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 833 of the COL3A1 protein. Computational prediction tool indicates that this variant may have a neutral impact on protein structure and function. 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 23/187998 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	RCV000181058	SCV001363407	likely benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.2498A>G (p.Lys833Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 156634 control chromosomes. The observed variant frequency is approximately 102-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2498A>G in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven (other) submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=6) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV000463723	SCV001522854	uncertain significance	Ehlers-Danlos syndrome, type 4	2019-11-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
All of Us Research Program, National Institutes of Health	RCV000463723	SCV004833691	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 833 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 been identified in 23/187998 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000463723	SCV005916633	uncertain significance	Ehlers-Danlos syndrome, type 4	2021-07-30	criteria provided, single submitter	research