Submissions for variant NM_005609.4(PYGM):c.645G>A (p.Lys215=)

gnomAD frequency: 0.00530  dbSNP: rs116315896

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081315	SCV000113233	benign	not specified	2012-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000081315	SCV000514329	benign	not specified	2016-10-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CeGaT Center for Human Genetics Tuebingen	RCV000585529	SCV000692713	benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	PYGM: BP4, BS1, BS2
Invitae	RCV000128552	SCV001113795	benign	Glycogen storage disease, type V	2024-02-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000585529	SCV001714988	uncertain significance	not provided	2022-10-26	criteria provided, single submitter	clinical testing	BS1, BP4
Genome-Nilou Lab	RCV000128552	SCV001737203	uncertain significance	Glycogen storage disease, type V	2021-05-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000081315	SCV002598814	likely benign	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: PYGM c.645G>A alters a non-conserved nucleotide resulting in a synonymous change. Consensus agreement among computational tools predict no significant impact on normal splicing, with 3/4 computational tools predicting the variant abolishes a cryptic exonic 5' donor site. Experimental evidence suggests that this variant may affect mRNA splicing as transcripts from peripheral blood mononuclear cells showed the inclusion of intron 6 and an altered reading frame (Garcia-Consuegra_2016). In muscle tissue, the normal transcript can be identified, although with an expression of only 5% relative to controls, suggesting a "leaky" splice effect (Garcia-Consuegra_2009). However, in both studies splicing was examined in samples from compound heterozygous patients with Glycogen Storage Disease Type V and to our knowledge, the variant effect on splicing has yet to be investigated in isolation in a controlled experimental system. The variant allele was found at a frequency of 0.0084 in 1614182 control chromosomes, including 73 homozygotes, in the gnomAD database, predominantly at a frequency of 0.01 within the Non-Finnish European subpopulation. The observed variant frequency within Non-Finnish European control individuals is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Nevertheless, c.645G>A has been reported in the literature in compound heterozygous individuals affected with Glycogen Storage Disease, Type V (Garcia-Consuegra_2009, Lucia_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22250184, 34426522, 26913921, 19251976). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Four submitters have classified the variant as benign/likely benign, three classified it as VUS and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV003298135	SCV004007190	likely benign	Inborn genetic diseases	2023-05-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV000128552	SCV004183526	uncertain significance	Glycogen storage disease, type V	2023-09-05	criteria provided, single submitter	clinical testing
GeneReviews	RCV000128552	SCV000172197	not provided	Glycogen storage disease, type V		no assertion provided	literature only
Illumina Laboratory Services, Illumina	RCV000128552	SCV000914530	pathogenic	Glycogen storage disease, type V	2019-01-09	flagged submission	clinical testing	The PYGM c.645G>A (p.Lys215) missense variant has been reported in at least three studies in which it has been found in a compound heterozygous state in at least five individuals with glycogen storage disease type V (GSDV) (García-Consuegra et al. 2009; Lucia et al. 2012; García-Consuegra et al. 2016). Two of these probands were brothers and two other of the probands also carried a second PYGM variant in cis with the p.Lys215 variant. The p.Lys215 variant was absent from 200 controls, but is reported at a frequency of 0.01869 in the Iberian populations in Spain from the 1000 Genomes Project. Clinical heterogeneity is observed in probands with GSDV: some probands have mild symptoms (fatigue or poor stamina) while others have a severe, rapidly progressing form that manifests shortly after birth. While the allele frequency for this variant in the population databases seems high compared to the disease prevalence, some probands may show mild symptoms and remain undiagnosed (De Castro et al. 2015). The p.Lys215 variant was shown by RT-PCR to disrupt splicing, causing inclusion of a 91-bp intron resulting in a change to the reading frame (García-Consuegra et al. 2016). Muscle biopsy tissue from probands carrying the variant showed 5% transcript levels compared to controls (García-Consuegra et al. 2009). Based on the collective evidence, the p.Lys215 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.
Natera, Inc.	RCV000128552	SCV001457729	uncertain significance	Glycogen storage disease, type V	2020-04-14	no assertion criteria provided	clinical testing