Submissions for variant NM_000090.4(COL3A1):c.284C>T (p.Pro95Leu)

gnomAD frequency: 0.00001  dbSNP: rs780260944

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000329215	SCV000425497	uncertain significance	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV001188676	SCV001355802	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 95 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 2/250840 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	RCV000329215	SCV001506667	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-02	criteria provided, single submitter	clinical testing	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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 333047). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is present in population databases (rs780260944, gnomAD 0.002%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 95 of the COL3A1 protein (p.Pro95Leu).
Ambry Genetics	RCV001188676	SCV002752716	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-07-21	criteria provided, single submitter	clinical testing	The p.P95L variant (also known as c.284C>T), located in coding exon 3 of the COL3A1 gene, results from a C to T substitution at nucleotide position 284. The proline at codon 95 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000329215	SCV004830716	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 95 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 2/250840 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.