Submissions for variant NM_017739.4(POMGNT1):c.1285-2A>G

dbSNP: rs386834012

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000292476	SCV000357990	likely pathogenic	POMGNT1-related disorder	2017-04-27	criteria provided, single submitter	clinical testing	The POMGNT1 c.1285-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1285-2A>G variant has been reported in three studies in which it is found in a total of three individuals with POMGNT1-related disorders, including in one in a homozygous state, in one in a compound heterozygous state, and in one in a heterozygous state in whom a second variant was not detected (Diesen et al. 2004; Biancheri et al. 2006; Mercuri et al. 2009). The c.1285-2A>G variant was absent from at least 125 controls but is reported at a frequency of 0.00002 in the European (non-Finnish) population of the Exome Aggregation Consortium. This frequency is based on one allele in an area of good sequence coverage so the variant is presumed to be rare. Based on the potential impact of splice acceptor variants and evidence from the literature, the c.1285-2A>G variant is classified as likely pathogenic for POMGNT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001853063	SCV002235667	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 15 of the POMGNT1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs386834012, gnomAD 0.0009%). Disruption of this splice site has been observed in individuals with congenital muscular dystrophy and/or muscle-eye-brain disease (PMID: 15466003, 17030669, 19299310). ClinVar contains an entry for this variant (Variation ID: 56578). 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.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002514260	SCV003761170	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The c.1285-2A>G variant in POMGNT1 has been previously reported in the literature in three individuals with muscular dystrophy-dystroglycanopathy (PMID: 19299310, 17030669, 15466003), and has been identified in 0.0009% (1/113576) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834012). 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#:56578) and has been interpreted as likely pathogenic/pathogenic by Invitae, Counsyl, and Illumina, probable-pathogenic by Juha Muilu Group (Institute for Molecular Medicine Finland (FIMM)), and as a variant of uncertain significance by Illumina. Of the three affected individuals, one of those was homozygous, which increases the likelihood that the c.1285-2A>G variant is pathogenic (PMID: 19299310). RT-PCR analysis performed on affected tissue shows intron retention and exon skipping (PMID: 17030669). 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. This variant is adjacent to an in-frame exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1_moderate, PS3, PM2_Supporting, PM3_supporting (Richards 2015).
Baylor Genetics	RCV003460639	SCV004206008	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-02-11	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049991	SCV000082400	probable-pathogenic	Muscle eye brain disease		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Illumina Laboratory Services, Illumina	RCV000375211	SCV000357989	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O	2017-04-27	flagged submission	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Counsyl	RCV000983991	SCV000800783	pathogenic	Retinitis pigmentosa 76	2017-08-22	no assertion criteria provided	clinical testing