Submissions for variant NM_001077365.2(POMT1):c.132A>C (p.Glu44Asp)

gnomAD frequency: 0.00002  dbSNP: rs398124244

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000177268	SCV000229112	likely pathogenic	not provided	2013-11-27	criteria provided, single submitter	clinical testing
Invitae	RCV001376971	SCV001574181	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 44 of the POMT1 protein (p.Glu44Asp). This variant is present in population databases (rs398124244, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital muscular dystrophy (PMID: 27159402). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 95456). 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 with a positive predictive value of 95%. This variant disrupts the p.Glu44 amino acid residue in POMT1. Other variant(s) that disrupt this residue have been observed in individuals with POMT1-related conditions (PMID: 27193224), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000177268	SCV002526472	likely pathogenic	not provided	2022-04-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27159402, 30564623)
Fulgent Genetics, Fulgent Genetics	RCV002477237	SCV002782030	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	2022-05-03	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000177268	SCV003813304	likely pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155069	SCV003844711	uncertain significance	not specified	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: POMT1 c.132A>C (p.Glu44Asp) results in a conservative amino acid change located in the glycosyl transferase family 39/83 domain (IPR003342) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251416 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.132A>C has been reported in the literature in the compound heterozygous state in two individuals affected with Dystrophinopathy (O'Grady_2016, Carlson_2017). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=1)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until additional clinical and/or functional evidence is available.
PreventionGenetics, part of Exact Sciences	RCV003407461	SCV004113553	likely pathogenic	POMT1-related condition	2023-04-17	criteria provided, single submitter	clinical testing	The POMT1 c.132A>C variant is predicted to result in the amino acid substitution p.Glu44Asp. This variant was reported in the compound heterozygous state in an individual with congenital muscular dystrophy (Table e-1 and e-3, Patient ID 102, O'Grady et al. 2016. PubMed ID: 27159402). Of note, another variant impacting the same amino acid was also reported in the compound heterozygous state in an individual with mild congenital muscular dystrophy [c.130G>A (pl.Glu44Lys), Case 3, Yang et al. 2016. PubMed ID: 27193224). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-134381510-A-C). This variant is interpreted as likely pathogenic.
Baylor Genetics	RCV003474682	SCV004204076	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2022-06-23	criteria provided, single submitter	clinical testing