Submissions for variant NM_130468.4(CHST14):c.878A>G (p.Tyr293Cys)

gnomAD frequency: 0.00001  dbSNP: rs121908258

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523135	SCV000617801	likely pathogenic	not provided	2017-10-04	criteria provided, single submitter	clinical testing	The Y293C likely pathogenic variant in the CHST14 gene has been reported in the homozygous state in a patient with adducted thumb-clubfoot syndrome (Dundar et al., 2009). This variant has also been reported a patient with dermatan 4-O-sulfotransferase 1 deficiency who also harbored an additional CHST14 variant in trans (Shimizu et al., 2011). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y293C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Finally, functional studies demonstrate that this variant leads to decreased sulfotransferase activity (Miyake et al., 2010).
Ambry Genetics	RCV002444414	SCV002682606	pathogenic	Cardiovascular phenotype	2020-06-12	criteria provided, single submitter	clinical testing	The p.Y293C pathogenic mutation (also known as c.878A>G), located in coding exon 1 of the CHST14 gene, results from an A to G substitution at nucleotide position 878. The tyrosine at codon 293 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified as homozygous or compound heterozygous in multiple individuals with dermatan 4-O-sulfotransferase 1 deficient Ehlers-Danlos Syndrome (D4ST1-deficient EDS) (Dündar M et al. Am. J. Hum. Genet., 2009 Dec;85:873-82; Miyake N et al. Hum. Mutat., 2010 Aug;31:966-74; Shimizu K et al. Am. J. Med. Genet. A, 2011 Aug;155A:1949-58). A functional study shows that this variant causes reduced sulfotransferase activity in transfected cells (Miyake N et al. Hum. Mutat., 2010 Aug;31:966-74). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000002429	SCV003442830	pathogenic	Ehlers-Danlos syndrome, musculocontractural type	2023-10-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 293 of the CHST14 protein (p.Tyr293Cys). This variant is present in population databases (rs121908258, gnomAD 0.007%). This missense change has been observed in individual(s) with clinical features of autosomal recessive CHST14-related conditions (PMID: 10766984, 20004762, 20533528, 21744491). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2339). 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. Experimental studies have shown that this missense change affects CHST14 function (PMID: 20004762). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV001290020	SCV000022587	pathogenic	Ehlers-Danlos syndrome, musculocontractural type 1	2010-08-01	no assertion criteria provided	literature only
UniProtKB/Swiss-Prot	RCV000002429	SCV000091174	not provided	Ehlers-Danlos syndrome, musculocontractural type		no assertion provided	not provided