rs267606993

Variant names:

• chr11-64759898-T-A
• rs267606993
• NM_005609.4:c.1A>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_005609.4(PYGM):​c.1A>T​(p.Met1?) variant causes a initiator codon 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 initiator_codon
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.93
• Publications: 13 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 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 47 pathogenic variants. Next in-frame start position is after 92 codons. Genomic position: 64758674. Lost 0.108 part of the original CDS.
• PS1: Another start lost variant in NM_005609.4 (PYGM) was described as [Pathogenic] in ClinVar
• 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 VariationId is 553271.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:2

May 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 553271). Disruption of the initiator codon has been observed in individuals with McArdle disease (PMID: 7951262, 9506549, 25740218, 28967462). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the PYGM mRNA. The next in-frame methionine is located at codon 92. -

Aug 10, 2017

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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
PhyloP100		5.9
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
PromoterAI		-0.21	Neutral
Varity_R		0.65
gMVP		0.56
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606993; hg19: chr11-64527370;