ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.367C>G (p.Gln123Glu) (rs142114921)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000197525 SCV000249868 uncertain significance not provided 2018-08-02 criteria provided, single submitter clinical testing p.Gln123Glu (Q123E) CAG>GAG: c.367 C>G in exon 3 of the COL5A1 gene (NM_000093.3)The Q123E variant in the COL5A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The Q123E variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts Q123E is damaging to the protein structure/function. The Q123E variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, missense mutations in nearby residues have not been reported in association with COL5A1-related disorders, suggesting this region of the protein may be tolerant of change. Additionally, the Q123E variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A1 gene, where the majority of missense mutations occur (Symoens et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.This variant was found in TAAD,TAADV2-1
Invitae RCV000233603 SCV000283486 uncertain significance Ehlers-Danlos syndrome, classic type 2019-07-22 criteria provided, single submitter clinical testing This sequence change replaces glutamine with glutamic acid at codon 123 of the COL5A1 protein (p.Gln123Glu). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and glutamic acid. This variant is present in population databases (rs142114921, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with a thoracic aortic aneurysm (PMID: 26854089) and in an individual affected with Ehlers-Danlos syndrome, classic type (PMID: 30858776). ClinVar contains an entry for this variant (Variation ID: 213011). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Illumina Clinical Services Laboratory,Illumina RCV000277979 SCV000478503 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000619794 SCV000738614 uncertain significance Cardiovascular phenotype 2016-05-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000233603 SCV000897494 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000233603 SCV001329742 likely benign Ehlers-Danlos syndrome, classic type 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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