Submissions for variant NM_130468.4(CHST14):c.635T>C (p.Val212Ala)

gnomAD frequency: 0.00046  dbSNP: rs144629123

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414071	SCV000492200	uncertain significance	not specified	2016-11-29	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the CHST14 gene. The V212A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V212A substitution occurs at a position that is conserved through mammals, and alanine (A) is not wild type in any species. In addition, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nonetheless, V212A is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Finally, this variant has been reported in approximately 0.1-0.2% of alleles from individuals of European ancestry in the NHLBI Exome Sequencing Project and the Exome Aggregation Consortium (ExAC), including three homozygous individuals.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086290	SCV000645323	benign	Ehlers-Danlos syndrome, musculocontractural type	2025-02-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585577	SCV000692805	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	CHST14: PP3, BS2
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278648	SCV002565439	uncertain significance	Ehlers-Danlos syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002365452	SCV002659035	likely benign	Cardiovascular phenotype	2022-05-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000414071	SCV005887672	benign	not specified	2025-01-22	criteria provided, single submitter	clinical testing	Variant summary: CHST14 c.635T>C (p.Val212Ala) results in a non-conservative amino acid change located in the Sulfotransferase family (IPR005331) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 1613726 control chromosomes, predominantly at a frequency of 0.0062 within the Ashkenazi Jewish subpopulation in the gnomAD database (v4), including 2 homozygotes. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 5.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHST14 causing Ehlers-Danlos syndrome, musculocontractural type phenotype (0.0011). To our knowledge, no occurrence of c.635T>C in individuals affected with Ehlers-Danlos syndrome, musculocontractural type and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 373593). Based on the evidence outlined above, the variant was classified as benign.