Submissions for variant NM_000232.5(SGCB):c.33+2T>A

dbSNP: rs2109380796

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001985768	SCV002265514	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E	2020-11-02	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, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 25862795). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change affects a donor splice site in intron 1 of the SGCB 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 SGCB are known to be pathogenic (PMID: 15938573, 18285821).
Neuberg Centre For Genomic Medicine, NCGM	RCV001985768	SCV004048301	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2E		criteria provided, single submitter	clinical testing	The splice site c.33+2T>A variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The variant is novel (not in any individuals) in 1000 Genomes. The nucleotide change in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic.