Submissions for variant NM_080605.4(B3GALT6):c.515C>T (p.Ala172Val)

gnomAD frequency: 0.00065  dbSNP: rs200646244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413594	SCV000491813	uncertain significance	not specified	2016-11-25	criteria provided, single submitter	clinical testing	The A172V variant in the B3GALT6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A172V variant was not observed with any significant frequency in approximately 5600 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A172V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, this substitution occurs at a position that is not conserved across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A172V as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000970550	SCV001118136	likely benign	Ehlers-Danlos syndrome, spondylodysplastic type, 2; Spondyloepimetaphyseal dysplasia with joint laxity	2025-01-29	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001579634	SCV001472163	uncertain significance	not provided	2019-09-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002523943	SCV003677059	likely benign	Inborn genetic diseases	2022-05-01	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.
CeGaT Center for Human Genetics Tuebingen	RCV001579634	SCV004126899	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000413594	SCV005883349	likely benign	not specified	2024-12-17	criteria provided, single submitter	clinical testing	Variant summary: B3GALT6 c.515C>T (p.Ala172Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 1350218 control chromosomes, predominantly at a frequency of 0.0013 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.16 fold of the estimated maximal expected allele frequency for a pathogenic variant in B3GALT6 causing Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures phenotype (0.0011). To our knowledge, no occurrence of c.515C>T in individuals affected with Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 373234). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579634	SCV001807957	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001579634	SCV001969482	likely benign	not provided		no assertion criteria provided	clinical testing