Submissions for variant NM_017739.4(POMGNT1):c.1895+1G>A

dbSNP: rs386834024

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001043665	SCV001207423	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 21 of the POMGNT1 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individuals with muscle-eye-brain disease (PMID: 15466003, 22554691, 28424332). ClinVar contains an entry for this variant (Variation ID: 56592). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Myriad Genetics, Inc.	RCV001810415	SCV002060143	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2021-11-16	criteria provided, single submitter	clinical testing	NM_017739.3(POMGNT1):c.1895+1G>A is a canonical splice variant classified as pathogenic in the context of POMGNT-related disorders. c.1895+1G>A has been observed in cases with relevant disease (PMID: 15466003, 26908613). Functional assessments of this variant are not available in the literature. c.1895+1G>A has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_017739.3(POMGNT1):c.1895+1G>A is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002513697	SCV003761148	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The c.1895+1G>A variant in POMGNT1 has been previously reported in one individual, in the compound heterozygous state, with muscular dystrophy-dystroglycanopathy (PMID: 15466003), and has been identified in 0.003% (1/30416) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs386834024). 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#:56592) and has been interpreted as pathogenic by multiple labs. This variant is located in the 5’ splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the POMGNT1 gene is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, although although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1_moderate, PM2, PM3 (Richards 2015).
Baylor Genetics	RCV001810415	SCV004206004	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-03-01	criteria provided, single submitter	clinical testing
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000050005	SCV000082414	probable-pathogenic	Muscle eye brain disease		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
OMIM	RCV000240866	SCV000299363	pathogenic	Retinitis pigmentosa 76	2012-07-15	no assertion criteria provided	literature only
Natera, Inc.	RCV000050005	SCV002089576	pathogenic	Muscle eye brain disease	2020-10-21	no assertion criteria provided	clinical testing