Submissions for variant NM_000090.4(COL3A1):c.3775G>A (p.Ala1259Thr)

gnomAD frequency: 0.00010  dbSNP: rs776478974

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001177066	SCV000319443	likely benign	Familial thoracic aortic aneurysm and aortic dissection	2021-10-05	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.
Illumina Laboratory Services, Illumina	RCV000321117	SCV000425543	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	RCV000321117	SCV000756047	likely benign	Ehlers-Danlos syndrome, type 4	2024-11-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177066	SCV001341194	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-12-12	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1259 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 been reported in two Chinese siblings affected with abdominal aortic aneurysm rupture and tissue fragility (PMID: 28035354) and was not detected in two unaffected family members. This variant has also been identified in one individual affected with vascular Ehlers-Danlos syndrome, having dissection of the right internal carotid artery (PMID: 25758994). This variant has also been identified in 29/282350 chromosomes (26/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for COL3A1-related disorders, 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.
GeneDx	RCV003328577	SCV004035554	uncertain significance	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Reported in association with vEDS and appears to segregate with aortopathy in one Chinese family (Frank et al., 2015; Zhang et al., 2017); 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); This variant is associated with the following publications: (PMID: 25758994, 28035354, 27153395, 34318601, 30919682, 36277156)
All of Us Research Program, National Institutes of Health	RCV000321117	SCV004827569	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-05-07	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 1259 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 been reported in two Chinese siblings affected with abdominal aortic aneurysm rupture and tissue fragility (PMID: 28035354) and was not detected in two unaffected family members. This variant has also been identified in one individual affected with vascular Ehlers-Danlos syndrome, having dissection of the right internal carotid artery (PMID: 25758994). This variant has also been identified in 29/282350 chromosomes (26/19954 East Asian chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the variant allele frequency is greater than expected for COL3A1-related disorders, 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003328577	SCV005408949	uncertain significance	not provided	2023-08-24	criteria provided, single submitter	clinical testing	BS1, PP2, PP3, PS4_moderate