ClinVar Miner

Submissions for variant NM_013382.5(POMT2):c.1997A>G (p.Tyr666Cys) (rs200198778)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genetic Medicine Research,Children's National Medical Center RCV000003376 SCV000265767 likely pathogenic Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B2 2015-12-01 criteria provided, single submitter research
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics 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 A, 1; 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 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000081569 SCV000196887 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing The Y666C pathogenic variant in the POMT2 gene has been reported previously in the homozygous state or in combination with another POMT2 variant in multiple individuals with features suggestive of POMT2-related disorder (Godfrey et al., 2007; Yanagisawa et al., 2007; Manya et al., 2008; Yanagisawa et al., 2009; Mercuri et al., 2009; Martinez et al., 2014; Punetha et al., 2016; Abdullah et al., 2017; Ostergaard et al., 2018). The Y666C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Y666C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret Y666C as a pathogenic variant.
Genetic Services Laboratory, University of Chicago RCV000193219 SCV000248592 pathogenic Muscular dystrophy 2015-07-01 criteria provided, single submitter clinical testing
Invitae RCV000648175 SCV000769989 pathogenic 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 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 666 of the POMT2 protein (p.Tyr666Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs200198778, ExAC 0.02%). This variant has been reported to be homozygous or compound heterozygous in families and individuals affected with congenital muscular dystrophy (PMID: 17634419, 17878297, 24002165). ClinVar contains an entry for this variant (Variation ID: 3221). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003376 SCV000023534 pathogenic Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B2 2009-07-01 no assertion criteria provided literature only
OMIM RCV000003377 SCV000023535 pathogenic Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A2 2009-07-01 no assertion criteria provided literature only
SIB Swiss Institute of Bioinformatics RCV000003376 SCV000803551 likely pathogenic Congenital muscular dystrophy-dystroglycanopathy with mental retardation, 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).

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