ClinVar Miner

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

gnomAD frequency: 0.00008  dbSNP: rs139660235
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Total submissions: 6
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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 uncertain significance Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 2019-02-06 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Invitae 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
PreventionGenetics, part of Exact Sciences RCV004542790 SCV004757235 likely pathogenic POMT1-related disorder 2023-12-01 criteria provided, single submitter 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.

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