ClinVar Miner

Submissions for variant NM_004130.4(GYG1):c.143+3G>C

gnomAD frequency: 0.00016  dbSNP: rs370652040
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000387284 SCV000329983 pathogenic not provided 2017-07-14 criteria provided, single submitter clinical testing The c.143+3 G>C splice site variant in the GYG1 gene has been previously reported in association with polyglucoasen body myopathy in several unrelated individuals who were homozygous for c.143+3 G>C or heterozygous for c.143+3 G>C and a second pathogenic variant in the GYG1 gene (Malfatti et al., 2014; Akman et al., 2016). Functional analysis of c.143+3 G>C found that it results in abnormal splicing, leading to skipping of exon 2 (Malfatti et al., 2014). Therefore, we interpret c.143+3 G>C to be a pathogenic variant.
Invitae RCV001054146 SCV001218447 pathogenic Glycogen storage disease XV; Polyglucosan body myopathy type 2 2024-01-10 criteria provided, single submitter clinical testing This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs370652040, gnomAD 0.04%). This variant has been observed in individuals with polyglucosan body myopathy (PMID: 25272951, 26652229, 29264399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2 and introduces a premature termination codon (PMID: 25272951). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Undiagnosed Diseases Network, NIH RCV001090151 SCV001245599 pathogenic Glycogen storage disease XV 2019-09-17 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000387284 SCV002024931 pathogenic not provided 2022-03-15 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000387284 SCV002586000 pathogenic not provided 2022-09-01 criteria provided, single submitter clinical testing GYG1: PP1:Strong, PM2, PM3, PS3:Moderate
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000150098 SCV003922104 likely pathogenic Polyglucosan body myopathy type 2 2023-05-02 criteria provided, single submitter curation The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in one individual with polyglucosan body myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162665), however the phase of these variants are unknown at this time. The c.143+3G>C variant has been previously reported in 16 unrelated individuals with polyglucosan body myopathy 2 (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156) and segregated with disease in 3 affected relatives in one family (PMID: 29264399), but has been identified in 0.04% (50/128982) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370652040). 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. Of these 16 previously reported unrelated individuals, 11 were homozygotes (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156), and one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 29264399), and the patient identified by our study was also a reported compound heterozygote who carried a pathogenic variant in unknown phase (ClinVar Variation ID: 162665), which increases the likelihood that the c.143+3G>C variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162661) and has been interpreted as pathogenic by the NIH Undiagnosed Disease Network, Invitae, CeGaT Center for Human Genetics Tuebingen, GeneDx, OMIM, and PerkinElmer Genomics. RT-PCR analysis of RNA from patient skeletal muscle tissue shows skipping of exon 2 and frameshift beginning at position 3 and leading to a premature termination codon 4 amino acids downstream (PMID: 25272951). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polyglucosan body myopathy 2. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015).
OMIM RCV000150098 SCV000196922 pathogenic Polyglucosan body myopathy type 2 2014-12-01 no assertion criteria provided literature only

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