ClinVar Miner

Submissions for variant NM_000093.5(COL5A1):c.4892C>T (p.Thr1631Met)

gnomAD frequency: 0.00006  dbSNP: rs764446683
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198222 SCV000249920 uncertain significance not provided 2019-05-16 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp RCV002225095 SCV000832809 benign Ehlers-Danlos syndrome, classic type, 1 2024-10-24 criteria provided, single submitter clinical testing
Mendelics RCV000703884 SCV001137952 uncertain significance Ehlers-Danlos syndrome, classic type 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000198222 SCV002050274 uncertain significance not provided 2020-11-20 criteria provided, single submitter clinical testing The COL5A1 c.4892C>T; p.Thr1631Met variant (rs764446683), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 213061). This variant is found on only six chromosomes (6/280962 alleles) in the Genome Aggregation Database. The threonine at codon 1631 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.622). However, given the lack of clinical and functional data, the significance of the p.Thr1631Met variant is uncertain at this time.
Molecular Genetics, Royal Melbourne Hospital RCV002225095 SCV002503809 uncertain significance Ehlers-Danlos syndrome, classic type, 1 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace threonine with methionine at codon 1631 of the COL5A1 protein, p.(Thr1631Met). The threonine residue is highly conserved (100 vertebrates, UCSC), and is located in the fibrillar collagen C-terminal domain. There is a moderate physicochemical difference between threonine and methionine. The variant is present in a large population cohort at a frequency of 0.002% (rs764446683, 6/280,962 alleles, 0 homozygotes in gnomAD v2.1), and has not been reported in the relevant clinical literature. It has been reported as a variant of uncertain significance (ClinVar ID: 213061), and identified in an individual with aortic dilatation and an individual with a possible connective tissue disorder (Invitae personal communication, Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 4/5 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP3.

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