Submissions for variant NM_001077365.2(POMT1):c.752C>T (p.Pro251Leu)

gnomAD frequency: 0.00008  dbSNP: rs139660235

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081495	SCV000113426	uncertain significance	not provided	2013-02-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764803	SCV000895948	uncertain significance	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	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001328597	SCV001519749	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1	2024-03-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001341723	SCV001535609	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 273 of the POMT1 protein (p.Pro273Leu). This variant is present in population databases (rs139660235, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (Invitae). 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: 95469). 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 80%. 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.
Revvity Omics, Revvity	RCV000081495	SCV003811834	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000081495	SCV005325962	uncertain significance	not provided	2024-03-16	criteria provided, single submitter	clinical testing	Reported in a study on the pathogencity of variants associated with limb girdle muscular dystrophy; listed as variant seen in the Leiden Open Variation Database, but no additional information was provided (PMID: 25898921); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34532947, 22522420, 25898921)
PreventionGenetics, part of Exact Sciences	RCV004542790	SCV004757235	likely pathogenic	POMT1-related disorder	2023-12-01	no assertion criteria provided	clinical testing	The POMT1 c.818C>T variant is predicted to result in the amino acid substitution p.Pro273Leu. This variant was reported in an individual with Walker-Warburg syndrome (reported as c.997C>T (p.Pro273Leu) in Table S1, Willer et al. 2012. PubMed ID: 22522420; Varagur et al. 2022. PubMed ID: 34801143). This variant was also reported in the homozygous state in a fetus with hydrocephalus and additional brain malformations (See #28697; https://assises-genetique.org/sessions-de-posters-affiches/). This variant has also been associated with limb girdle muscular dystrophies, but further information was not available (Table S2, Di Fruscio et al. 2015. PubMed ID: 25898921). Functional studies in patient-derived fibroblast cell lines suggest that this variant might affect normal protein function (reported as POMT1-WWS in Figure 5 and Table S1, Willer et al. 2012. PubMed ID: 22522420). At PreventionGenetics, we have observed the c818C>T variant in the homozygous state in an individual with hydrocephalus and another patient in the compound heterozygous state with a clear pathogenic, loss-of-function variant POMT1 variant (internal data). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/95469/). We interpret this variant as likely pathogenic.