Submissions for variant NM_013382.7(POMT2):c.881A>G (p.Tyr294Cys)

gnomAD frequency: 0.00002  dbSNP: rs587780423

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118041	SCV000152368	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2N	2014-02-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000497603	SCV000589921	likely pathogenic	not provided	2017-06-15	criteria provided, single submitter	clinical testing	A likely pathogenic variant has been identified in the POMT2 gene. The Y294C variant has recently been reported in the homozygous state in multiple individuals with hypotonia, scoliosis, intellectual disability, and hyperdontia in a consanguineous family in the published literature (Riazuddin et al., 2016). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y294C 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. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with POMT2-related disorders (Stenson et al., 2014). Therefore, the R294C variant is now classified as a likely pathogenic variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778739	SCV002014981	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2021-10-19	criteria provided, single submitter	clinical testing	Variant summary: POMT2 c.881A>G (p.Tyr294Cys) results in a non-conservative amino acid change located in the Glycosyl transferase family 39/83 domain (IPR003342) 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 4e-06 in 251434 control chromosomes (gnomAD). c.881A>G has been reported in the literature in at least one individual affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (Song_2021). Furthermore, the variant was reported in 4 homozygous individuals from a consanguineous family with features of moderate to severe intellectual disability with speech delay, hyperdontia, moderate hypotonia and scoliosis (Riazuddin_2017). 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. A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003474722	SCV004204087	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2	2023-10-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005008018	SCV005635519	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	2024-03-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000497603	SCV003809718	uncertain significance	not provided	2022-11-10	flagged submission	clinical testing