Submissions for variant NM_080605.4(B3GALT6):c.588dup (p.Arg197fs)

dbSNP: rs533071750

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000488976	SCV000577762	likely pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Frameshift variant in a single exon gene predicted to result in an altered/extended protein product, as the last 133 amino acids are lost and replaced with 245 incorrect amino acids; Observed with another variant on the opposite allele (in trans) in two related individuals with spEDS referred for genetic testing at GeneDx; Other frameshift variants have been reported in the Human Gene Mutation Database in association with spEDS, including one affecting the same residue and resulting in a premature termination codon 81 residues downstream (c.588delG, p.(Arg197AlafsX81)) (PMID: 23664117, 34529350, 29931299); This variant is associated with the following publications: (PMID: 34529350, 23664117, 29931299)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001267718	SCV001445971	uncertain significance	Spondyloepimetaphyseal dysplasia with joint laxity, type 1, with or without fractures	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg197fsAlaTer246 variant in B3GALT6 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 986387), in two siblings with spondyloepimetaphyseal dysplasia with joint laxity, type 1. Familial genome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 986387). The p.Arg197fsAlaTer246 version in B3GALT6 has been previously reported in one individual with spondyloepimetaphyseal dysplasia with joint laxity, type 1, but has been identified in 0.04% (10/22694) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs533071750). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. The affected individual previously reported was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 34529350, ClinVar ID: 60493), which increases the likelihood that the p.Arg197fsAlaTer246 variant is pathogenic. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 197 and leads to a premature termination codon 246 amino acids downstream. This gene is a single exon gene and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While there is some evidence to suggest that loss of function of the B3GALT6 gene is a disease mechanism in autosomal recessive spondyloepimetaphyseal dysplasia with joint laxity, type 1, this association is not yet strongly established based on the criteria laid out in Tayoun, 2018 (PMID: 30192042). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_Supporting, PM3 (Richards 2015).
DASA	RCV001824140	SCV002073759	likely pathogenic	Al-Gazali syndrome	2022-02-05	criteria provided, single submitter	clinical testing	The c.588dup;p.(Arg197Alafs*246) is a null frameshift variant (NMD) in the B3GALT6 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1_strong. This variant is not present in population databases (rs533071750, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856913	SCV002148899	uncertain significance	Ehlers-Danlos syndrome, spondylodysplastic type, 2; Spondyloepimetaphyseal dysplasia with joint laxity	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the B3GALT6 gene (p.Arg197Alafs*246). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 133 amino acid(s) of the B3GALT6 protein and extend the protein by 112 additional amino acid residues. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This frameshift has been observed in individual(s) with clinical features of B3GALT6-related conditions (PMID: 34529350). ClinVar contains an entry for this variant (Variation ID: 427130). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant results in an extension of the B3GALT6 protein. Other variant(s) that result in a similarly extended protein product (p.Ile328Hisfs*115) have been observed in individuals with B3GALT6-related disease (Invitae). This suggests that these extensions may be clinically significant. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000488976	SCV005411940	uncertain significance	not provided	2023-10-13	criteria provided, single submitter	clinical testing	PVS1_strong