Submissions for variant NM_013382.7(POMT2):c.1997A>G (p.Tyr666Cys)

gnomAD frequency: 0.00010  dbSNP: rs200198778

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081569	SCV000196887	pathogenic	not provided	2020-08-06	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 17634419, 30060766, 24002165, 19299310, 28980384, 29175898, 17878207, 19138766, 17869517, 27854218, 32115343, 31127727, 31589614, 32528171)
Genetic Services Laboratory, University of Chicago	RCV000193219	SCV000248592	pathogenic	Muscular dystrophy	2015-07-01	criteria provided, single submitter	clinical testing
Center for Genetic Medicine Research, Children's National Medical Center	RCV000003376	SCV000265767	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	2015-12-01	criteria provided, single submitter	research
Eurofins Ntd Llc (ga)	RCV000081569	SCV000331113	pathogenic	not provided	2017-01-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515301	SCV000611299	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
Invitae	RCV000648175	SCV000769989	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	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 666 of the POMT2 protein (p.Tyr666Cys). This variant is present in population databases (rs200198778, gnomAD 0.02%). This missense change has been observed in individuals with congenital muscular dystrophy (PMID: 17634419, 17878297, 24002165). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3221). 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 POMT2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
SIB Swiss Institute of Bioinformatics	RCV000003376	SCV000803551	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy-dystroglycanopathy (congenital with mental retardation), type B, 2, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3 => For recessive disorders, detected in trans with a pathogenic variant (PMID:17634419,19138766). PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:17878207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Found in multiple unrelated patients (PMID:17878207,17634419,19138766,19299310).
Revvity Omics, Revvity	RCV000081569	SCV002019498	pathogenic	not provided	2022-05-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398429	SCV004104804	pathogenic	POMT2-related disorder	2023-03-14	criteria provided, single submitter	clinical testing	The POMT2 c.1997A>G variant is predicted to result in the amino acid substitution p.Tyr666Cys. This variant has been reported in the homozygous or compound heterozygous state in many individuals with POMT2-related disorders (Yanagisawa et al. 2007. PubMed ID: 17634419; Godfrey et al. 2007. PubMed ID: 17878207; Martinez et al. 2013. PubMed ID: 24002165; Østergaard et al. 2017. PubMed ID: 29175898; Westra et al. 2019. PubMed ID: 31127727; Saat et al. 2021. PubMed ID: 33963534; Punetha et al. 2016. PubMed ID: 27854218). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-77745107-T-C). This variant is interpreted as pathogenic.
Baylor Genetics	RCV000003377	SCV004204084	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	2024-03-30	criteria provided, single submitter	clinical testing
OMIM	RCV000003376	SCV000023534	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2	2009-07-01	no assertion criteria provided	literature only
OMIM	RCV000003377	SCV000023535	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	2009-07-01	no assertion criteria provided	literature only