ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.805G>A (p.Glu269Lys) (rs761079177)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724142 SCV000231473 uncertain significance not provided 2014-09-01 criteria provided, single submitter clinical testing
GeneDx RCV000724142 SCV000249876 uncertain significance not provided 2020-08-19 criteria provided, single submitter clinical testing Has been reported as a variant of uncertain significance in a patient with a history of ectopia lentis, hypermobility, aortic dilation, and mitral valve prolapse, who also carried a variant in the FBN1 gene (Weerakkody et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; Stenson et al., 2014); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 198041; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27011056, 33206719)
Ambry Genetics RCV000251555 SCV000320285 likely benign Cardiovascular phenotype 2020-10-07 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,Illumina RCV000403793 SCV000478514 uncertain significance Ehlers-Danlos syndrome, type 7A 2016-06-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000724142 SCV000885242 uncertain significance not provided 2018-01-16 criteria provided, single submitter clinical testing The COL5A1 p.Glu269Lys variant (rs761079177) has not been reported in the medical literature, nor has it been previously identified in our laboratory; however, it is listed in the ClinVar database as a variant of uncertain significance (Variation ID: 198041). This variant is observed in the general population with an overall allele frequency of 0.02% (58/246,206 alleles) in the Genome Aggregation Database. The glutamic acid at codon 269 is well conserved across 12 species (Alamut v.2.10.0), but computational algorithms do not reach a consensus as to the effect of this variant (SIFT: damaging, PolyPhen-2: benign, Mutation Taster: disease causing). Therefore, based on the available information, the clinical significance of the p.Glu269Lys variant cannot be determined with certainty.
Invitae RCV000818780 SCV000959412 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 269 of the COL5A1 protein (p.Glu269Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs761079177, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with suspected Ehlers–Danlos syndrome (PMID: 27011056). ClinVar contains an entry for this variant (Variation ID: 198041). 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: "Benign"; 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 RCV000818780 SCV001332500 likely benign Ehlers-Danlos syndrome, classic type 2018-01-13 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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