Submissions for variant NM_017739.4(POMGNT1):c.1212-3_1212-2del

dbSNP: rs1064797111

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000487672	SCV000574759	likely pathogenic	not provided	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378216	SCV001575743	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2020-07-03	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 14 of the POMGNT1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with POMGNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 424898). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Molecular Genetics, Royal Melbourne Hospital	RCV001788235	SCV002029242	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2021-12-02	criteria provided, single submitter	clinical testing	This sequence change in POMGNT1 occurs within the canonical splice acceptor site (-2) of intron 14. It is predicted to cause an in-frame deletion (removes amino acids 405-407) that is predicted to escape nonsense mediated decay and remove <10% of the protein. This variant is present in a single individual in gnomAD v2.1 (1/18,386 alleles) in the East Asian population, which is consistent with a recessive condition. To our knowledge, this variant has not been reported in the literature in any individuals with POMGNT1-related disease. It has been reported as likely pathogenic (ClinVar Variation ID: 424898). This variant has been observed in trans with the variant c.385C>T, p.(Arg129Trp) which is classified as likely pathogenic in an individual with muscular dystrophy (Royal Melbourne Hospital). Based on the classification scheme RMH Modified ACMG Guidelines v1.4.0, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PVS1_Moderate, PM3, PM2_Supporting.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002526998	SCV003761173	uncertain significance	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The c.1212-3_1212-2del variant in POMGNT1 has been reported in one individual, in the compound heterozygous state, with muscular dystrophy-dystroglycanopathy (ClinVar accession number SCV002029242.2), and has been identified in 0.005% (1/18386) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1064797111). 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#:424898) and has been interpreted as likely pathogenic by Invitae and CeGaT Center for Human Genetics Tuebingen and as a variant of uncertain significance by Royal Melbourne Hospital Molecular Genetics. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 9 bases from the intron-exon boundary, providing evidence that this variant may delete 3 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1_moderate, PM2_supporting, PM3 (Richards 2015).