ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.226A>G (p.Asn76Asp) (rs142045411)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000619676 SCV000738525 uncertain significance Cardiovascular phenotype 2017-09-02 criteria provided, single submitter clinical testing The p.N76D variant (also known as c.226A>G), located in coding exon 2 of the COL3A1 gene, results from an A to G substitution at nucleotide position 226. The asparagine at codon 76 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000634709 SCV000756044 uncertain significance Ehlers-Danlos syndrome, type 4 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 76 of the COL3A1 protein (p.Asn76Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs142045411, ExAC 0.01%). This variant has not been reported in the literature in individuals with COL3A1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Clinical Services Laboratory,Illumina RCV000634709 SCV001298980 benign Ehlers-Danlos syndrome, type 4 2018-01-12 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.
Color Health, Inc RCV001180581 SCV001345540 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-02-19 criteria provided, single submitter clinical testing This missense variant replaces asparagine with aspartic acid at codon 76 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 been reported in an individual affected with lacunar stroke (PMID: 31719132). This variant has been identified in 19/282052 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 RCV001251398 SCV001426984 likely benign not specified 2020-07-20 criteria provided, single submitter clinical testing Variant summary: COL3A1 c.226A>G (p.Asn76Asp) results in a conservative amino acid change located in the von Willebrand factor (VWF) type C domain (IPR001007) of the encoded protein sequence. Four of fvie in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.7e-05 in 282052 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 80-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.226A>G, has been reported in the literature in an individual affected with lacunar stroke (Tan_2019). This report however, does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome, Vascular Type. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and 3 classified the variant as VUS, while one called it as benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001570822 SCV001795179 uncertain significance not provided 2020-10-16 criteria provided, single submitter clinical testing Reported in an individual with younger-onset small vessel disease (Tan et al., 2019); Reported in ClinVar (ClinVar Variant ID# 519601; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 31719132)

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