rs786204482

Positions:

• chr11-64751626-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_005609.4(PYGM):​c.1797del​(p.Phe599LeufsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PYGM NM_005609.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.361

Genes affected

PYGM (HGNC:9726): (glycogen phosphorylase, muscle associated) This gene encodes a muscle enzyme involved in glycogenolysis. Highly similar enzymes encoded by different genes are found in liver and brain. Mutations in this gene are associated with McArdle disease (myophosphorylase deficiency), a glycogen storage disease of muscle. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64751626-CA-C is Pathogenic according to our data. Variant chr11-64751626-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64751626-CA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1797del	p.Phe599LeufsTer6	frameshift_variant	15/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1533del	p.Phe511LeufsTer6	frameshift_variant	13/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1797del	p.Phe599LeufsTer6	frameshift_variant	15/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.1533del	p.Phe511LeufsTer6	frameshift_variant	13/18	2		ENSP00000366650
PYGM	ENST00000462303.1	n.121del		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251198 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461698 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727126

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:3

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	May 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 05, 2023	This sequence change creates a premature translational stop signal (p.Phe599Leufs*6) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs769960481, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 14748827). ClinVar contains an entry for this variant (Variation ID: 188807). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2023	Variant summary: PYGM c.1797delT (p.Phe599LeufsX6) 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. Truncations downstream of this position have been classified as pathogenic in ClinVar and are associated with McArdle disease in HGMD. The variant allele was found at a frequency of 4e-06 in 251198 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1797delT has been reported in the literature in at least one individual affected with McArdle disease/Glycogen Storage Disease, Type V (e.g., Martin_2004). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs769960481; hg19: chr11-64519098;