Submissions for variant NM_000090.4(COL3A1):c.217G>C (p.Asp73His)

gnomAD frequency: 0.00006  dbSNP: rs200246388

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000771273	SCV000319286	benign	Familial thoracic aortic aneurysm and aortic dissection	2023-12-21	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.
Illumina Laboratory Services, Illumina	RCV000264796	SCV000425496	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000264796	SCV000541783	likely benign	Ehlers-Danlos syndrome, type 4	2023-10-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000520803	SCV000620150	uncertain significance	not provided	2022-08-11	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 has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD)
Color Diagnostics, LLC DBA Color Health	RCV000771273	SCV000903418	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 73 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one case died of sudden and unexplained thoracic aortic aneurysm and dissection (Kathiravel 2014, dissertation, University of Gottfried Wilhelm Leibniz). This variant has also been identified in 35/282090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary 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	RCV002278228	SCV002565622	uncertain significance	Ehlers-Danlos syndrome	2019-06-01	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000264796	SCV004830639	likely benign	Ehlers-Danlos syndrome, type 4	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 73 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one case died of sudden and unexplained thoracic aortic aneurysm and dissection (Kathiravel 2014, dissertation, University of Gottfried Wilhelm Leibniz). This variant has also been identified in 35/282090 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary 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	RCV004701353	SCV005203828	likely benign	not specified	2024-07-02	criteria provided, single submitter	clinical testing	Variant summary: COL3A1 c.217G>C (p.Asp73His) results in a non-conservative amino acid change located in the VWFC domain (IPR001007) 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 0.00014 in 250708 control chromosomes, predominantly at a frequency of 0.00075 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 600 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06). To our knowledge, no occurrence of c.217G>C in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 263844). Based on the evidence outlined above, the variant was classified as likely benign.