Submissions for variant NM_001077365.2(POMT1):c.314G>A (p.Arg105His)

dbSNP: rs1554772469

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	RCV004529018	SCV002041720	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2024-03-11	criteria provided, single submitter	clinical testing	Variant summary: POMT1 c.314G>A (p.Arg105His) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251458 control chromosomes. c.314G>A has been reported in the literature as a homozygous genotype in at least two individuals (likely siblings) affected with Walker-Warburg syndrome (example, van Reeuwijk_2006). This report has subsequently been cited by others (example, Geis_2019). It is also recognized that the phenotypic spectrum for POMT1 ranges from the severe Walker Warburg syndrome (WWS) to milder forms of limb girdle muscular dystrophy (LGMD). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications has been ascertained in the context of this evaluation (PMID: 31311558, 16575835). ClinVar contains an entry for this variant (Variation ID: 1329035). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003772194	SCV004592692	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2023-06-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 105 of the POMT1 protein (p.Arg105His). 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. This variant disrupts the p.Arg105 amino acid residue in POMT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16575835, 27193224). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POMT1 protein function. ClinVar contains an entry for this variant (Variation ID: 1329035). This missense change has been observed in individual(s) with Walker-Warburg syndrome (PMID: 16575835). This variant is present in population databases (no rsID available, gnomAD 0.0009%).
Fulgent Genetics, Fulgent Genetics	RCV005040388	SCV005674890	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1	2024-03-13	criteria provided, single submitter	clinical testing