Submissions for variant NM_001077365.2(POMT1):c.1272+1G>A

dbSNP: rs2131751359

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553600	SCV001774515	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2021-07-20	criteria provided, single submitter	clinical testing	Variant summary: POMT1 c.1338+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 5 splicing donor site. Experimental evidence supports these predictions demonstrating the variant leads to the loss of exon 13 and a frameshift change (Bouchet_2007, Hu_2017). The variant was absent in 251274 control chromosomes (gnomAD). c.1338+1G>A has been reported in the literature in individuals/families affected with muscular dystrophy-dystroglycanopathy (Bouchet_2007, Hu_2017); evidence of co-segregation with disease in a family was provided by one of the studies (Hu_2017). These data indicate that the variant is likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003474006	SCV004204043	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2023-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003771694	SCV004591545	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2023-02-06	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 1192212). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. Disruption of this splice site has been observed in individual(s) with POMT1-related conditions (PMID: 17559086, 28157257). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This sequence change affects a donor splice site in intron 13 of the POMT1 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 POMT1 are known to be pathogenic (PMID: 12369018, 15637732, 16575835). This variant is not present in population databases (gnomAD no frequency).