Submissions for variant NM_013382.7(POMT2):c.1261C>T (p.Arg421Trp)

gnomAD frequency: 0.00002  dbSNP: rs727502855

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000594145	SCV000704253	pathogenic	not provided	2018-02-14	criteria provided, single submitter	clinical testing
Invitae	RCV000699248	SCV000827950	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N	2023-06-14	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 162597). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT2 protein function. This missense change has been observed in individuals with clinical features of POMT2-related conditions (PMID: 27854218, 30060766, 31127727, 33200426, 34413876). This variant is present in population databases (rs727502855, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 421 of the POMT2 protein (p.Arg421Trp).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004950	SCV001164475	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2N	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731484	SCV001983638	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2021-09-21	criteria provided, single submitter	clinical testing	Variant summary: POMT2 c.1261C>T (p.Arg421Trp) results in a non-conservative amino acid change located in the MIR motif domain (IPR016093) 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 2.4e-05 in 251482 control chromosomes. c.1261C>T has been reported in the literature as a compound heterozygous genotype in comprehensively genotyped (WES/panel based analysis) and well phenotyped set of individuals affected with Autosomal Recessive Limb-Girdle Muscular Dystrophy and has been subsequently cited by others (example, Johnson_2018, Ostergaard_2018, Topf_2020, Song_2021). 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002498687	SCV002811469	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N	2021-08-09	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000594145	SCV003809784	uncertain significance	not provided	2019-07-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474801	SCV004204106	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	2024-03-13	criteria provided, single submitter	clinical testing