Submissions for variant NM_000090.4(COL3A1):c.203A>G (p.Asp68Gly)

gnomAD frequency: 0.00001  dbSNP: rs376603102

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000709865	SCV000233341	uncertain significance	not provided	2024-01-03	criteria provided, single submitter	clinical testing	Reported as a heterozygous variant in an individual with aortic dilation (Morgan et al., 2020); 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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000541054	SCV000631639	uncertain significance	Ehlers-Danlos syndrome, type 4	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 68 of the COL3A1 protein (p.Asp68Gly). This variant is present in population databases (rs376603102, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 199708). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000771906	SCV000904670	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 68 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 COL3A1-related disorders in the literature. This variant has been identified in 6/250758 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.
Fulgent Genetics, Fulgent Genetics	RCV002478602	SCV002779813	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-10-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000541054	SCV004830605	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 68 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 6/250758 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000541054	SCV005400364	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene. Dominant-negative is due to missense variants affecting glycine residues in the Gly-X-Y repeat within the triple helical region, while loss-of-function is due to null alleles (PMID: 29346445). (I) 0108 - This gene is associated with both recessive and dominant disease; There is currently no genotype-phenotype correlation between autosomal dominant Ehlers-Danlos syndrome (EDS), vascular type (MIM#130050) and autosomal recessive polymicrogyria with or without vascular-type EDS (MIM#618343). (I) 0112 - The condition associated with this gene has incomplete penetrance. This is associated with COL3A1 null variants (PMID: 20301667). (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301667). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated von Willebrand factor C domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The substitution to glutamic acid (p.Asp68Glu) has been reported as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS in ClinVar and in a paper where it was identified in a male paediatric cardiology patient (ClinVar, Morgan et al. (2020)). (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
GenomeConnect, ClinGen	RCV000709865	SCV000840200	not provided	not provided		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.