Submissions for variant NM_000090.4(COL3A1):c.3208G>T (p.Ala1070Ser)

gnomAD frequency: 0.00001  dbSNP: rs376738516

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000634717	SCV000756054	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1070 of the COL3A1 protein (p.Ala1070Ser). This variant is present in population databases (rs376738516, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 529320). 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 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.
Fulgent Genetics, Fulgent Genetics	RCV002483794	SCV002789725	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2022-03-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003528216	SCV004363020	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1070 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 observed in individual(s) with clinical features of COL3A1-related conditions (ClinVar SCV000756054.2). 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.
All of Us Research Program, National Institutes of Health	RCV000634717	SCV004829450	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 1070 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 observed in individual(s) with clinical features of COL3A1-related conditions (ClinVar SCV000756054.2). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788049	SCV005399267	uncertain significance	Ehlers-Danlos syndrome, dominant type 4	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL3A1-related disease. Missense variants affecting glycine residues within the collagen triple helical region exert a dominant negative effect, while null alleles result in haploinsufficiency which may confer delayed onset and a milder clinical course (PMID: 21637106; 29346445). (I) 0108 - This gene is associated with both recessive and dominant disease. Vascular Ehlers-Danlos syndrome (EDS), AD; Polymicrogyria with or without vascular EDS, AR (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated triple helical region but does not affect a glycine residue (Decipher). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign