rs769960481

Variant names:

• chr11-64751626-CA-C
• rs769960481
• NM_005609.4:c.1797delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_005609.4(PYGM):​c.1797delT​(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
• Publications: 2 publications found

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]

PYGM Gene-Disease associations (from GenCC):

• glycogen storage disease V

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1797delT	p.Phe599LeufsTer6	frameshift_variant	Exon 15 of 20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1533delT	p.Phe511LeufsTer6	frameshift_variant	Exon 13 of 18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1797delT	p.Phe599LeufsTer6	frameshift_variant	Exon 15 of 20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.1533delT	p.Phe511LeufsTer6	frameshift_variant	Exon 13 of 18	2		ENSP00000366650.3
PYGM	ENST00000462303.1	n.121delT		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251198 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111888

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

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

May 31, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Jan 20, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.36
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs769960481; hg19: chr11-64519098; COSMIC: COSV51225306; COSMIC: COSV51225306;