ClinVar Miner

Submissions for variant NM_130468.4(CHST14):c.784G>A (p.Glu262Lys)

gnomAD frequency: 0.00002  dbSNP: rs1247205097
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000500082 SCV000594125 likely pathogenic Ehlers-Danlos syndrome, musculocontractural type 2016-09-15 criteria provided, single submitter clinical testing
GeneDx RCV001561424 SCV001784029 likely pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing Reported in ClinVar as likely pathogenic by another clinical laboratory (ClinVar Variant ID#434766; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26373698, 25348902, 28346368, 31905796, 32629534, 34815299, 26582918)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000500082 SCV001983683 likely pathogenic Ehlers-Danlos syndrome, musculocontractural type 2021-09-28 criteria provided, single submitter clinical testing Variant summary: CHST14 c.784G>A (p.Glu262Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251416 control chromosomes. c.784G>A has been reported in the literature two siblings affected with Ehlers-Danlos Syndrome, Musculocontractural Type, in the homozygous state (Janecke_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000500082 SCV002974311 pathogenic Ehlers-Danlos syndrome, musculocontractural type 2023-12-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 262 of the CHST14 protein (p.Glu262Lys). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with musculocontractural type Ehlers-Danlos syndrome (PMID: 25348902, 26373698, 34815299; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 434766). 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 expected to disrupt CHST14 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV003962376 SCV004782312 likely pathogenic CHST14-related disorder 2023-10-30 criteria provided, single submitter clinical testing The CHST14 c.784G>A variant is predicted to result in the amino acid substitution p.Glu262Lys. This variant has been reported in the homozygous state in multiple individuals with musculocontractural Ehlers-Danlos syndrome (Janecke et al. 2016. PubMed ID: 26373698; Table S2, Minatogawa et al. 2021. PubMed ID: 34815299). This variant is reported in 0.0031% of alleles in individuals of European (non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-40764196-G-A). This variant is interpreted as likely pathogenic.
OMIM RCV002271341 SCV002555555 pathogenic Ehlers-Danlos syndrome, musculocontractural type 1 2022-07-27 no assertion criteria provided literature only

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