Submissions for variant NM_017739.4(POMGNT1):c.643C>T (p.Arg215Ter)

gnomAD frequency: 0.00001  dbSNP: rs386834034

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002272048	SCV000484423	pathogenic	Muscular dystrophy-dystroglycanopathy	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with POMGNT1-related disorders. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic and likely pathogenic in ClinVar in individuals with POMGNT1-related disorders. (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV000578838	SCV000680688	pathogenic	not provided	2017-06-14	criteria provided, single submitter	clinical testing	The R215X variant in the POMGNT1 gene has been reported previously in the homozygous state in an individual with severe intellectual disability, hypotonia, pachygyria, polymicrogyria, and seizures (Stark et al., 2016). It has also been reported in the compound heterozygous state, along with a second nonsense variant, in an individual with muscle eye brain disease (Saredi et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R215X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R215X as a pathogenic variant.
Invitae	RCV001062800	SCV001227623	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg215*) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs386834034, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 22554691, 26938784, 28832562). 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: 56604). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000578838	SCV002544277	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	POMGNT1: PVS1, PM3:Strong, PM2
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002272048	SCV003761187	pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg215Ter variant in POMGNT1 has been reported in at least two individuals with muscular dystrophy-dystroglycanopathy (PMID: 22554691, 26938784), and has been identified in 0.006% (2/34582) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834034). 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 also been reported in ClinVar (Variation ID#: 56604) and has been interpreted as pathogenic/likely pathogenic by multiple labs. Of the two affected individuals reported, one was a compound heterozygote who carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg215Ter variant is pathogenic (PMID: 22554691, ClinVarID: 56610). cDNA sequencing analysis performed on affected tissue shows exon 7 skipping, which is out-of-frame exon (PMID:22554691). This nonsense variant leads to a premature termination codon at position 215, which is predicted to lead to a truncated or absent protein. 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: PVS1, PM2_supporting, PM3, PS3 (Richards 2015).
Baylor Genetics	RCV003460643	SCV004205949	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-10-24	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050017	SCV000082426	probable-pathogenic	Muscle eye brain disease		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Counsyl	RCV000050017	SCV001132463	likely pathogenic	Muscle eye brain disease	2014-01-02	no assertion criteria provided	clinical testing
Counsyl	RCV000408610	SCV001132464	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2014-01-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984294	SCV001132465	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O	2014-01-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984295	SCV001132466	likely pathogenic	Retinitis pigmentosa 76	2014-01-02	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000050017	SCV002089625	pathogenic	Muscle eye brain disease	2020-10-01	no assertion criteria provided	clinical testing