Submissions for variant NM_013382.7(POMT2):c.1785G>A (p.Pro595=)

gnomAD frequency: 0.00004  dbSNP: rs202237807

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000658699	SCV000780485	uncertain significance	not provided	2018-01-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000658699	SCV000861013	uncertain significance	not provided	2018-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000658699	SCV001758706	uncertain significance	not provided	2022-11-30	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001855380	SCV002268541	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N	2022-09-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 595 of the POMT2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POMT2 protein. This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. This variant is present in population databases (rs202237807, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with POMT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 546745). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509493	SCV002819918	uncertain significance	not specified	2022-12-30	criteria provided, single submitter	clinical testing	Variant summary: POMT2 c.1785G>A (p.Pro595Pro) alters a non-conserved nucleotide, which is the last nucleotide of exon 17, and therefore could affect mRNA splicing, leading to a significantly altered protein sequence: 3/4 computational tools predict this variant weakens the 5' donor site, while 1 predicts no impact, but these predictions have not been confirmed by functional assays. The variant allele was found at a frequency of 3.6e-05 in 250750 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1785G>A in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.