Submissions for variant NM_130468.4(CHST14):c.1033C>T (p.Arg345Trp)

dbSNP: rs372422727

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519446	SCV000616678	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000509210	SCV001533744	uncertain significance	Ehlers-Danlos syndrome, musculocontractural type	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 345 of the CHST14 protein (p.Arg345Trp). This variant is present in population databases (rs372422727, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CHST14-related conditions. ClinVar contains an entry for this variant (Variation ID: 440975). 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 not expected to disrupt CHST14 protein function. 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.
Ambry Genetics	RCV002395232	SCV002696789	uncertain significance	Cardiovascular phenotype	2024-05-20	criteria provided, single submitter	clinical testing	The c.1033C>T (p.R345W) alteration is located in exon 1 (coding exon 1) of the CHST14 gene. This alteration results from a C to T substitution at nucleotide position 1033, causing the arginine (R) at amino acid position 345 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000519446	SCV004227363	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005239110	SCV005886629	uncertain significance	not specified	2025-02-04	criteria provided, single submitter	clinical testing	Variant summary: CHST14 c.1033C>T (p.Arg345Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250516 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHST14 causing Ehlers-Danlos syndrome, musculocontractural type (0.00014 vs 0.0011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1033C>T in individuals affected with Ehlers-Danlos syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 440975). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen	RCV000509210	SCV000606991	not provided	Ehlers-Danlos syndrome, musculocontractural type		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.