Submissions for variant NM_017739.4(POMGNT1):c.636C>T (p.Phe212=)

gnomAD frequency: 0.00002  dbSNP: rs190057175

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255207	SCV000322258	pathogenic	not provided	2023-03-25	criteria provided, single submitter	clinical testing	Has been reported previously in homozygous and compound heterozygous patients with POMGNT1-related disorders (Bouchet et al., 2007; Oliveira et al., 2008; Valencia et al., 2013); Functional studies indicate that c.636 C>T leads to skipping of exon 7, which results in a frameshift and reduced levels of POMGNT1 protein as compared to controls (Oliveira et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18330676, 17559086, 22323514, 23326386, 19299310, 28424332, 28492532, 32627857, 31589614, 35175440)
Invitae	RCV000695969	SCV000824510	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change affects codon 212 of the POMGNT1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the POMGNT1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs190057175, gnomAD 0.006%). This variant has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 17559086, 18330676, 22323514, 23326386, 28424332). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265399). Studies have shown that this variant results in skipping of exon 7 and introduces a premature termination codon (PMID: 17559086, 18330676). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255207	SCV001249300	pathogenic	not provided	2019-11-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255207	SCV002019483	pathogenic	not provided	2019-12-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500958	SCV002809794	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3; Retinitis pigmentosa 76	2021-09-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002518761	SCV003761191	pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The c.636C>T (p.Phe212=) variant in POMGNT1 has been reported in six individuals with muscular dystrophy-dystroglycanopathy (PMID 23326386, PMID 28424332, PMID 22323514, PMID 17559086, PMID 18330676) and has been identified in 0.01004% (2/19924) East Asian chromosomes in gnomAD (dbSNP ID rs190057175). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has been reported in ClinVar (Variation ID #265399) as pathogenic by GeneDx, Invitae, Counsyl, CeGaT Center for Human Genetics Tuebingen, Natera, Inc, and Perkin-Elmer Genomics. Of these six affected individuals, one was a homozygote (PMID: 18330676) and two were compound heterozygotes, one confirmed compound heterozygote who carried a pathogenic variant in confirmed trans (PMID: 28424332) and one compound heterozygote who carried a likely pathogenic variant in trans (PMID: 22323514), which increases the likelihood that the c.636C>T (p.Phe212=) variant is pathogenic. The variant was shown by RT-PCR analysis (PMID: 18330676, PMID: 17559086) and muscle RNAseq of patient tissue (PMID: 28424332) to alter splicing and lead to exon skipping of exon 7, frameshift, and premature truncation. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_supporting, PS3_Strong (Richards 2015).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155140	SCV003844688	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2023-02-02	criteria provided, single submitter	clinical testing	Variant summary: POMGNT1 c.636C>T alters a conserved nucleotide resulting in a synonymous change. 1/4 computational tools predicted weakening of the canonical 5' splice donor site. Multiple reports have demonstrated that this silent variant leads to exon 7 skipping, when analyzed at the RNA level (examples: Cummings_2017 and Oliveira_2008). The variant allele was found at a frequency of 4e-05 in 251122 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in POMGNT1 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4e-05 vs 0.00072), allowing no conclusion about variant significance. c.636C>T has been reported in the literature in individuals affected with muscular dystrophy and lissencephaly (examples: Bouchet_2007, Cummings_2017 and Oliveira_2008). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003463717	SCV004205953	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-10-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000984296	SCV001132467	likely pathogenic	Muscle eye brain disease	2014-01-23	no assertion criteria provided	clinical testing
Counsyl	RCV000984297	SCV001132468	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2014-01-23	no assertion criteria provided	clinical testing
Counsyl	RCV000984298	SCV001132469	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O	2014-01-23	no assertion criteria provided	clinical testing
Counsyl	RCV000984299	SCV001132470	likely pathogenic	Retinitis pigmentosa 76	2014-01-23	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000984296	SCV001461201	pathogenic	Muscle eye brain disease	2020-09-16	no assertion criteria provided	clinical testing