ClinVar Miner

Submissions for variant NM_001077365.2(POMT1):c.1698+1G>A

gnomAD frequency: 0.00002  dbSNP: rs763586263
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000778149 SCV000914281 uncertain significance POMT1-related disorder 2019-04-05 criteria provided, single submitter clinical testing The POMT1 c.1764+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1764+1G>A variant has been reported in two studies in which it is found in a compound heterozygous state with a missense/splice variant in one fetus with cobblestone lissencephaly (Bouchet et al. 2007; Devisme et al. 2012). Control data are unavailable for this variant, which is reported at a frequency of 0.000061 in the South Asian population from the Exome Aggregation Consortium; however, this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. RNA analysis showed that the c.1764+1G>A variant causes aberrant splicing, resulting in a transcript lacking exon 17 (Bouchet et al. 2007). Based on the evidence and the potential impact of splice donor variants, the c.1764+1G>A variant is classified as a variant of unknown significance but suspicious for pathogenicity for POMT1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV001040545 SCV001204125 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2K; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B1; Walker-Warburg congenital muscular dystrophy 2023-08-10 criteria provided, single submitter clinical testing Disruption of this splice site has been observed in individual(s) with clinical features of Walker-Warburg syndrome (PMID: 17559086, 22323514). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 631540). This variant is present in population databases (rs763586263, gnomAD 0.003%). This sequence change affects a donor splice site in intron 17 of the POMT1 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 POMT1 are known to be pathogenic (PMID: 12369018, 15637732, 16575835).
Revvity Omics, Revvity RCV001784380 SCV002019489 pathogenic not provided 2023-03-28 criteria provided, single submitter clinical testing
GeneDx RCV001784380 SCV002562361 likely pathogenic not provided 2022-08-09 criteria provided, single submitter clinical testing Reported previously with another variant in POMT1 (phase unknown) in a fetus with type II lissencephaly, retinal dysplasia, and limb/visceral malformations in published literature; however, no segregation information was provided (Bouchet et al., 2007; Devisme et al., 2012); Canonical splice site variant expected to result in aberrant splicing, with RNA studies performed in a fetus with this variant demonstrating a transcript without exon 17 (Bouchet et al., 2007); Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 16575835, 15637732, 12369018, 22549409, 22323514, 17559086)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002469286 SCV002766345 likely pathogenic Autosomal recessive limb-girdle muscular dystrophy 2022-11-16 criteria provided, single submitter clinical testing Variant summary: POMT1 c.1764+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, demonstrating in a patient derived sample that the variant resulted in an in-frame skipping of exon 17 (Bouchet_2007), with a predicted protein level effect of p.Trp551_Ser588del, which would affect the C-terminal four TM domain (amino acids 542-740; IPR032421) of the protein. The variant allele was found at a frequency of 8e-06 in 250470 control chromosomes (gnomAD). The variant, c.1764+1G>A, has been reported in the literature in compound heterozygous state in a fetus affected with cobblestone lissencephaly (Bouchet_2007, Devisme_2012). Four submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=1), likely pathogenic (n=2), or unknown significance but suspicious for pathogenicity (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV003461048 SCV004206062 likely pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1 2023-08-05 criteria provided, single submitter clinical testing

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