Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000490077 | SCV000577451 | pathogenic | not provided | 2022-03-08 | criteria provided, single submitter | clinical testing | Previously reported in individuals with POMGNT1-related disorders who harbor an additional POMGNT1 variant referred for genetic testing at GeneDx and in published literature (Diesen et al., 2004; Devisme et al., 2012; Saredi et al., 2012); Published functional studies demonstrate the splice defect leads to retention of intron 21 (Saredi et al., 2012); Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 29555514, 32115343, 22554691, 25525159, 17906881, 15466003, 19299310, 22323514, 28424332) |
Labcorp Genetics |
RCV000704718 | SCV000833678 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 21 of the POMGNT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs386834024, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with muscular dystrophy-dystroglycanopathy (PMID: 15466003, 22554691, 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: 56593). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in partial inclusion of intron 21 (also known as intron 25) and introduces a new termination codon (PMID: 28424332). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
Illumina Laboratory Services, |
RCV000778243 | SCV000914412 | pathogenic | POMGNT1-related disorder | 2018-05-03 | criteria provided, single submitter | clinical testing | The POMGNT1 c.1895+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in at least four studies in which it is found in a compound heterozygous state in three individuals with muscle-eye-brain disease and in one individual with cobblestone lissencephaly (Diesen et al. 2004; Mercuri et al. 2009; Saredi et al. 2012; Devisme et al. 2012). The variant was absent from at least 125 control individuals and is reported at a frequency of 0.00047 in the European (non-Finnish) population of the Exome Aggregation Consortium. RT-PCR experiments demonstrated that the variant affects splicing with retention of the intron between exons 21 and 22 (Saredi et al. 2012). Due to the potential impact of splice donor variants and the evidence from the literature, the c.1895+1G>T variant is classified as pathogenic for POMGNT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
Broad Center for Mendelian Genomics, |
RCV001005010 | SCV001164571 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O | 2018-12-03 | criteria provided, single submitter | research | The homozygous c.1895+1G>T variant in POMGNT1 was identified by our study in one individual with limb-girdle muscular dystrophy (LGMD). This variant has been identified in 0.007982% (22/275604) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs386834024). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide some evidence that the c.1895+1G>T variant may impact protein function with abnormal splicing and reduced translation (PMID: 22554691). However, these types of assays may not accurately represent biological function. This variant has been observed in the compound heterozygous state, with two variants not reported in ClinVar, in 2 individuals with LGMD as reported by the literature (PMID: 22554691, 22323514). The presence of this variant in combination with a reported pathogenic variant and in an individual with LGMD increases the likelihood that the c.1895+1G>T variant is pathogenic. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences reported in the literature in individuals with LGMD. ACMG/AMP Criteria applied: PM2, PVS1, PS3 (Richards 2015). |
Centre for Mendelian Genomics, |
RCV001005010 | SCV001368122 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O | 2019-08-21 | criteria provided, single submitter | clinical testing | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. |
Ambry Genetics | RCV001266790 | SCV001444969 | pathogenic | Inborn genetic diseases | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Revvity Omics, |
RCV000490077 | SCV002019481 | pathogenic | not provided | 2020-03-22 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV001810416 | SCV002060325 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 | 2021-10-27 | criteria provided, single submitter | clinical testing | NM_017739.3(POMGNT1):c.1895+1G>T is a canonical splice variant classified as pathogenic in the context of muscle-eye-brain disease. c.1895+1G>T has been observed in cases with relevant disease (PMID: 15466003, 19299310, 22323514, 28688748, 22554691). Functional assessments of this variant are available in the literature (PMID: 22554691). c.1895+1G>T has been observed in population frequency databases (gnomAD: FIN 0.02%). In summary, NM_017739.3(POMGNT1):c.1895+1G>T 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. |
Victorian Clinical Genetics Services, |
RCV002470741 | SCV002767662 | pathogenic | Myopathy caused by variation in POMGNT1 | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, 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 POMGNT-related disorders. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0205 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with less than 1/3 of the protein sequence affected. (SP) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to result in intron 21 retention and a premature termination codon (PMID: 22554691; 28424332) (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 22 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative nucleotide change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other canonical splice variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar; PMID: 26908613). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with POMGNT1-related disorders (ClinVar; PMID: 22323514, 15466003, 28688748, 29555514, 28424332, 22554691) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Broad Center for Mendelian Genomics, |
RCV002513698 | SCV003761147 | likely pathogenic | Muscular dystrophy-dystroglycanopathy | 2023-01-24 | criteria provided, single submitter | curation | The c.1895+1G>T variant in POMGNT1 has been previously reported in eight individuals with muscular dystrophy-dystroglycanopathy (PMID: 32115343, PMID: 29555514, PMID: 28688748, PMID: 22323514, PMID: 19299310, PMID: 15466003, PMID: 22554691, PMID: 28424332), and has been identified in 0.012% (15/128292) non-Finnish European 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 not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#:56593) and has been interpreted as pathogenic by Illumina (most recent interpretation; previously interpreted as VUS [2016] and likely pathogenic [2016]), Ambry Genetics, Centre for Mendelian Genomics,University Medical Centre Ljubljana, Broad Institute Rare Disease Group,GeneDx, Invitae, Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), Myriad Women's Health, Inc., Natera, Inc, PerkinElmer Genomics, and Counsyl. Of these eight affected individuals, one was a compound heterozygote who carried a pathogenic variant with unknown phase (PMID: 29555514) and one was a compound heterozygote who carried a likely pathogenic variant with unknown phase (PMID: 22323514), which increases the likelihood that the c.1895+1G>T variant is pathogenic. The variant was shown by RT-PCR analysis (PMID: 22554691) and muscle RNAseq of patient tissue (PMID: 28424332) to alter splicing and lead to intron retention between exons 21 and 22. 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 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, PM3 (Richards 2015). |
Baylor Genetics | RCV001810416 | SCV004205952 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 | 2024-03-18 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005025105 | SCV005647625 | 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 | 2024-05-23 | criteria provided, single submitter | clinical testing | |
Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000050006 | SCV000082415 | probable-pathogenic | Muscle eye brain disease | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. | |
Natera, |
RCV000050006 | SCV001460152 | pathogenic | Muscle eye brain disease | 2020-09-16 | no assertion criteria provided | clinical testing | |
Prevention |
RCV000778243 | SCV004741883 | pathogenic | POMGNT1-related disorder | 2024-02-14 | no assertion criteria provided | clinical testing | The POMGNT1 c.1895+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in several unrelated individuals with muscle-eye-brain disease (see for example, Saredi et al. 2012. PubMed ID: 22554691; Diesen et al. 2004. PubMed ID: 15466003). Functional RNA studies on this variant have shown it leads to retention of intron 21 (Saredi et al. 2012. PubMed ID: 22554691). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in POMGNT1 are expected to be pathogenic. This variant is interpreted as pathogenic. |