11-64759898-T-C

Position:

• chr11-64759898-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PS1_Moderate PM2 PP5_Very_Strong

The NM_005609.4(PYGM):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000616 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PYGM NM_005609.4 start_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.93

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 20 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_005609.4 (PYGM) was described as [Pathogenic] in ClinVar as 156341
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64759898-T-C is Pathogenic according to our data. Variant chr11-64759898-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64759898-T-C is described in Lovd as [Pathogenic]. Variant chr11-64759898-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.1A>G	p.Met1?	start_lost	1/20	ENST00000164139.4
PYGM	NM_001164716.1	c.1A>G	p.Met1?	start_lost	1/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.1A>G	p.Met1?	start_lost	1/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.1A>G	p.Met1?	start_lost	1/18	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 250944 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135748

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: 0.0000265

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727114

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:5

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Apr 11, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 13, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2309). Disruption of the initiator codon has been observed in individual(s) with McArdle disease (PMID: 9506549, 25740218, 28967462). This variant is present in population databases (rs267606993, gnomAD 0.004%). This sequence change affects the initiator methionine of the PYGM mRNA. The next in-frame methionine is located at codon 92. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Nov 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 15, 2015	- -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.77
Sift	Benign	0.22	T;D
Sift4G	Uncertain	0.039	D;D
Polyphen		1.0	.;D
Vest4		0.84
MutPred		1.0		Loss of MoRF binding (P = 0.1195);Loss of MoRF binding (P = 0.1195);
MVP		0.94
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs267606993; hg19: chr11-64527370;