ClinVar Miner

Submissions for variant NM_001077365.2(POMT1):c.1698+1G>A (rs763586263)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778149 SCV000914281 uncertain significance POMT1-Related Disorders 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 likely pathogenic Limb-girdle muscular dystrophy-dystroglycanopathy, type C1; Congenital muscular dystrophy-dystroglycanopathy with mental retardation, type B1; Walker-Warburg congenital muscular dystrophy 2019-03-29 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 17 of the POMT1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs763586263, ExAC 0.006%). This variant has been observed in a fetus affected with clinical features of Walker-Warburg syndrome (PMID: 17559086). Donor and acceptor splice site variants 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). 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.

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