ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.2262del (p.Lys754fs) (rs398124210)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000081311 SCV000226789 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing
GeneDx RCV000081311 SCV000322084 pathogenic not provided 2018-09-17 criteria provided, single submitter clinical testing The c.2262delA variant in the PYGM gene has been reported multiple times in association with McArdle disease (Kubisch et al., 1998; Bruno et al., 2006; Rubio et al., 2007; de Luna et al., 2014). The deletion causes a frameshift starting with codon Lysine 754, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 49 of the new reading frame, denoted p.Lys754AsnfsX49. This variant is predicted to cause loss of normal protein function through protein truncation. Therefore, c.2262delA is considered a pathogenic variant.
Counsyl RCV000175318 SCV000677967 pathogenic Glycogen storage disease, type V 2015-09-10 criteria provided, single submitter clinical testing
Invitae RCV000175318 SCV000821021 pathogenic Glycogen storage disease, type V 2018-12-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PYGM gene (p.Lys754Asnfs*49). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acids of the PYGM protein. This variant is present in population databases (rs398124210, ExAC 0.04%). This variant has been reported to segregate with McArdle disease in a family (PMID: 9633816). It has also been reported to be homozygous or compund heterozygous in multiple affected individuals with the same condition (PMID: 22250184, 17324573). ClinVar contains an entry for this variant (Variation ID: 95296). For these reasons, this variant has been classified as Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000175318 SCV000915540 likely pathogenic Glycogen storage disease, type V 2018-10-25 criteria provided, single submitter clinical testing The PYGM c.2262delA (p.Lys754AsnfsTer49) variant results in a frameshift, and is predicted to result in premature termination of the protein. The p.Lys754AsnfsTer49 variant has been reported in at least eleven studies in which it is found in a total of 35 individuals including in 22 in a compound heterozygous state, eight in a heterozygous state and five in a homozygous state (Kubisch et al. 1998; Bruno et al. 2006; Aquaron et al. 2007; Rubio et al. 2007; Rubio et al. 2007; Deschauer et al. 2007; Nogales-Gadea et al. 2008; García-Benítez et al. 2013; de Luna et al. 2014; Hogrel et al. 2015; Inal-Gültekin et al. 2017). At least 12 of the compound heterozygotes carried the same stop-gained variant on the second allele (p.Arg50Ter). This genotype was shown to result in null myophosphorylase activity (García-Benítez et al. 2013; de Luna et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00691 in the European American population of the Exome Sequencing Project. Although this allele frequency appears high based on disease prevalence, the symptoms of glycogen storage disease type V are typically mild, and some probands may be asymptomatic, suggesting that the disorder may be underdiagnosed. Based on the evidence from the literature, the p.Lys754AsnfsTer49 variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000175318 SCV000996067 pathogenic Glycogen storage disease, type V 2017-08-04 criteria provided, single submitter clinical testing This frameshifting variant that is predicted to result in premature truncation of the protein. This variant has been listed as pathogenic by two separate clinical laboratories in the ClinVar database. Additionally, this variant has been reported in multiple affected patients in the compound heterozygous state (reviewed in PMID: 17915571). The highest reported allele frequency in the ExAC database is 0.00036 in the South Asian population. Thus, it is presumed to be rare. Based on the combined evidence, this variant is classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000081311 SCV000801328 pathogenic not provided 2017-04-24 no assertion criteria provided clinical testing

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