ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.4340A>G (p.Tyr1447Cys)

gnomAD frequency: 0.00001  dbSNP: rs1407784923
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002314212 SCV000738510 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2016-01-12 criteria provided, single submitter clinical testing The p.Y1447C variant (also known as c.4340A>G), located in coding exon 51 of the COL3A1 gene, results from an A to G substitution at nucleotide position 4340. The tyrosine at codon 1447 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001037289 SCV001200695 uncertain significance Ehlers-Danlos syndrome, type 4 2022-06-20 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. 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. ClinVar contains an entry for this variant (Variation ID: 519596). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1447 of the COL3A1 protein (p.Tyr1447Cys).
All of Us Research Program, National Institutes of Health RCV001037289 SCV004838241 uncertain significance Ehlers-Danlos syndrome, type 4 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 1447 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 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.

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