Submissions for variant NM_000090.4(COL3A1):c.4003G>A (p.Gly1335Ser)

gnomAD frequency: 0.00001  dbSNP: rs751807135

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001190246	SCV000319888	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-02	criteria provided, single submitter	clinical testing	The c.4003G>A (p.G1335S) alteration is located in exon 49 (coding exon 49) of the COL3A1 gene. This alteration results from a G to A substitution at nucleotide position 4003, causing the glycine (G) at amino acid position 1335 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001190246	SCV001357696	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1335 of the COL3A1 protein. Computational prediction tool indicates that this variant may have an uncertain impact on protein structure and function. 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 2/251340 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001337142	SCV001530731	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1335 of the COL3A1 protein (p.Gly1335Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of COL3A1-related conditions (internal data). ClinVar contains an entry for this variant (Variation ID: 264160). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
GeneDx	RCV003441828	SCV004168917	uncertain significance	not provided	2023-10-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (gnomAD); 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)
All of Us Research Program, National Institutes of Health	RCV001337142	SCV004825564	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1335 in the C-terminal propeptide sequence 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 not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 2/251340 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535494	SCV001749442	not provided	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-11-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.