Submissions for variant NM_152490.5(B3GALNT2):c.842-1G>A

gnomAD frequency: 0.00001  dbSNP: rs764784497

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001993480	SCV002255771	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2022-08-23	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1467731). This variant has not been reported in the literature in individuals affected with B3GALNT2-related conditions. This variant is present in population databases (rs764784497, gnomAD 0.003%). This sequence change affects an acceptor splice site in intron 7 of the B3GALNT2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in B3GALNT2 are known to be pathogenic (PMID: 23453667).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001993480	SCV004020391	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 11	2023-06-14	criteria provided, single submitter	clinical testing	Variant summary: B3GALNT2 c.842-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 3 prime canonical acceptor site and three predict the variant strengthens/creates a 3 prime cryptic acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.8e-05 in 216592 control chromosomes in GnomAD. To our knowledge, no occurrence of c.842-1G>A in individuals affected with Muscular Dystrophy-Dystroglycanopathy 11 (congenital With Brain And Eye Anomalies) Type A and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.