Submissions for variant NM_152490.5(B3GALNT2):c.824_825dup (p.Ile276fs)

dbSNP: rs367543075

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000119390	SCV000568240	pathogenic	not provided	2024-12-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29273094, 35456500, 31980526, 34906519, 23453667)
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625390	SCV000745211	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2017-05-31	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625390	SCV000745854	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2017-10-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000625390	SCV000826128	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile276Leufs*26) in the B3GALNT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in B3GALNT2 are known to be pathogenic (PMID: 23453667). This variant is present in population databases (rs367543075, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with congenital muscular dystrophy and/or congenital muscular dystrophy-dystroglycanopathy (PMID: 23453667, 29273094). It has also been observed to segregate with disease in related individuals. This variant is also known as c.822_823dup. ClinVar contains an entry for this variant (Variation ID: 132981). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV000625390	SCV002025106	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2019-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000625390	SCV003923305	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: B3GALNT2 c.824_825dupTT (p.Ile276LeufsX26) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00021 in 251380 control chromosomes (gnomAD). c.824_825dupTT has been reported in the literature in the compound heterozygous state in individuals affected with and/or with features of Muscular Dystrophy-Dystroglycanopathy (congenital With Brain And Eye Anomalies) and in two siblings presenting with mild intellectual disability and behavioral problems but without muscular involvement (e.g. Stevens_2013, Maroofian_2017, Marangoni_2022). These data indicate that the variant is likely to be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function found the variant failed to restore IIH6 staining in a complementation assay, resulting in <10% of WT activity (Maroofian_2017). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=4)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000625390	SCV004697571	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2024-02-28	criteria provided, single submitter	clinical testing	second B3GALNT2 in trans (Missense-Variant, VUS)
Leiden Muscular Dystrophy pages (B3GALNT2)	RCV000119390	SCV000154297	not provided	not provided		no assertion provided	not provided
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000119390	SCV001963010	pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745196	SCV005365835	pathogenic	B3GALNT2-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The B3GALNT2 c.824_825dupTT variant is predicted to result in a frameshift and premature protein termination (p.Ile276Leufs*26). This variant has been reported in the compound heterozygous state to be causative for dystroglycanopathy in two unrelated families (Stevens et al. 2013. PubMed ID: 23453667; Maroofian et al. 2017. PubMed ID: 29273094). This variant is reported in 0.043% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in B3GALNT2 are expected to be pathogenic, and this variant has been interpreted as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/132981). Given all the evidence, we too interpret c.824_825dup (p.Ile276Leufs*26) as pathogenic.