rs267606993

Positions:

• chr11-64759898-T-A
• chr11-64759898-T-C
• chr11-64759898-T-G

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>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYGM NM_005609.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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 [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64759898-T-A is Pathogenic according to our data. Variant chr11-64759898-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 553271.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1A>T	p.Met1?	start_lost	1/20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1A>T	p.Met1?	start_lost	1/18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1A>T	p.Met1?	start_lost	1/20	1	NM_005609.4	ENSP00000164139	P1
PYGM	ENST00000377432.7	c.1A>T	p.Met1?	start_lost	1/18	2		ENSP00000366650

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 15, 2022	This sequence change affects the initiator methionine of the PYGM mRNA. The next in-frame methionine is located at codon 92. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with McArdle disease (PMID: 7951262, 9506549, 25740218, 28967462). ClinVar contains an entry for this variant (Variation ID: 553271). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.19	.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D;D
PROVEAN	Benign	-1.4	N;N
REVEL	Pathogenic	0.75
Sift	Benign	0.034	D;D
Sift4G	Benign	0.064	T;T
Polyphen		1.0	.;D
Vest4		0.82
MutPred		1.0		Loss of MoRF binding (P = 0.0672);Loss of MoRF binding (P = 0.0672);
MVP		0.93
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.65
gMVP		0.56

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;