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

dbSNP: rs398124210

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081311	SCV000226789	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000081311	SCV000322084	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 89 amino acids are replaced with 48 different amino acids, and other loss-of-function variants have been reported downstream in HGMD; This variant is associated with the following publications: (PMID: 14748827, 21802952, 11168025, 17994553, 17915571, 17324573, 22832773, 25740218, 16786513, 17221871, 9633816, 25240406, 17404776, 28967462, 29143597, 9506549, 29926259, 29749052, 29350794, 30011114, 22250184, 31517061, 31019026, 31589614, 31319225, 34426522, 34534370, 33072517, 35465342)
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	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys754Asnfs*49) in the PYGM gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 89 amino acid(s) of the PYGM protein. This variant is present in population databases (rs398124210, gnomAD 0.03%). This premature translational stop signal has been observed in individuals with McArdle disease (PMID: 9633816, 17324573, 22250184). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 95296). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, 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.
CeGaT Center for Human Genetics Tuebingen	RCV000081311	SCV001247778	pathogenic	not provided	2020-02-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000175318	SCV002019590	pathogenic	Glycogen storage disease, type V	2021-08-18	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000175318	SCV002802806	pathogenic	Glycogen storage disease, type V	2021-11-10	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000175318	SCV004207214	pathogenic	Glycogen storage disease, type V	2023-10-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000175318	SCV004240964	pathogenic	Glycogen storage disease, type V	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.2262delA (p.Lys754AsnfsX49) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00012 in 251484 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.2262delA has been reported in the literature in individuals affected with Glycogen Storage Disease, Type V (e.g. Aquaron_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 17324573). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000081311	SCV000801328	pathogenic	not provided	2017-04-24	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000175318	SCV001461270	pathogenic	Glycogen storage disease, type V	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000081311	SCV001806973	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081311	SCV001972284	likely pathogenic	not provided		no assertion criteria provided	clinical testing