ClinVar Miner

Submissions for variant NM_013382.5(POMT2):c.1261C>T (rs727502855)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000594145 SCV000704253 pathogenic not provided 2018-02-14 criteria provided, single submitter clinical testing
Invitae RCV000699248 SCV000827950 uncertain significance Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A2; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B2; Limb-girdle muscular dystrophy-dystroglycanopathy, type C2 2019-04-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 421 of the POMT2 protein (p.Arg421Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs727502855, ExAC 0.01%). This variant has been observed in combination with another POMT2 variant in several individuals affected with POMT2-related conditions (PMID: 27854218, 30060766). ClinVar contains an entry for this variant (Variation ID: 162597). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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.
Broad Institute Rare Disease Group,Broad Institute RCV001004950 SCV001164475 likely pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C2 2018-12-03 criteria provided, single submitter research The heterozygous p.Arg421Trp variant in POMT2 was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in two siblings with limb-girdle muscular dystrophy (LGMD). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant has been identified in 0.01299% (4/30782) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727502855). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported pathogenic by OMIM in ClinVar (Variation ID: 424827). The presence of this variant in combination with a likely pathogenic variant (described earlier) and a frameshift variant (reported in the literature) in 3 individuals with LGMD increases the likelihood that the p.Arg421Trp variant is pathogenic (PMID: 27854218). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PP1, PP3, PM3 (Richards 2015).

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