ClinVar Miner

Submissions for variant NM_000093.4(COL5A1):c.2096C>T (p.Thr699Met) (rs142313124)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757120 SCV000885241 uncertain significance not provided 2018-05-06 criteria provided, single submitter clinical testing The COL5A1 c.2096C>T; p.Thr699Met variant (rs142313124), to our knowledge, has not been described in the medical literature but is reported as likely benign by multiple laboratories in ClinVar (Variation ID: 213040) and is observed in the general population at an overall frequency of 0.06% (172/276942 alleles) in the Genome Aggregation Database. The threonine at codon 699 is highly conserved, but computational algorithms (PolyPhen-2, SIFT) predict that this variant is tolerated. Due to limited information regarding this variant, its clinical significance cannot be determined with certainty. Pathogenic variants of COL5A1 are associated with autosomal dominant Ehlers-Danlos syndrome, classic type (MIM: 130000).
Ambry Genetics RCV000617228 SCV000738584 likely benign Cardiovascular phenotype 2017-09-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000196358 SCV000861395 likely benign not specified 2018-05-22 criteria provided, single submitter clinical testing
GeneDx RCV000196358 SCV000249899 likely benign not specified 2017-12-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000302769 SCV000478541 likely benign Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000468094 SCV000549016 uncertain significance Ehlers-Danlos syndrome, classic type 2018-06-15 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 699 of the COL5A1 protein (p.Thr699Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs142313124, ExAC 0.09%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 213040). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.

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