rs116987552

Variant names:

• chr11-64759751-G-A
• rs116987552
• NM_005609.4:c.148C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-64759751-G-A
• chr11-64759751-G-C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 20P and 2B. PVS1 PS3 PP5_Very_Strong BS1_Supporting BS2_Supporting

The NM_005609.4(PYGM):​c.148C>T​(p.Arg50*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,614,240 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000373042: A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012).; SCV000626780: Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID:22730558).; SCV000713109: "This variant causes glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015)."; SCV001980710: Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008).; SCV002761410: "Well-established functional studies show a delerious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease )" (PS3).; SCV005875624: Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. PMID:22730558.; SCV000329478: Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); PMID:25873271; SCV001554240: Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID:25873271).; SCV000740891: A knock-in mouse model homozygous for the p.R50* alteration was generated which has the same muscle phenotype as McArdle patients, including undetectable myophosphorylase protein and activity in skeletal muscle, massive muscle glycogen accumulation, hyperCKaemia and very poor exercise performance (Nogales-Gadea, 2012).". Synonymous variant affecting the same amino acid position (i.e. R50R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (10 hom.)
• Consequence: PYGM NM_005609.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:36 O:2
• Conservation: PhyloP100: 2.56
• Publications: 108 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: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000373042: A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012).; SCV000626780: Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558).; SCV000713109: "This variant causes glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015)."; SCV001980710: Sequencing and RT-PCR studies have suggested that the c.148C>T variant is subject to nonsense mediated decay as mature cDNA transcript were not detected from this allele in individuals harboring these variant (Nogales-Gadea et al., 2008).; SCV002761410: "Well-established functional studies show a delerious effect of this variant ( Nogales-Gadea (2012) PubMed: 22730558 Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease )" (PS3).; SCV005875624: Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. PMID: 22730558.; SCV000329478: Mouse model, homozygous for R50X, found to have undetectable myophosphorylase protein and enzyme activity in skeletal muscle as well as massive muscle glycogen accumulation (Brull et al., 2015); PMID: 25873271; SCV001554240: Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271).; SCV000740891: A knock-in mouse model homozygous for the p.R50* alteration was generated which has the same muscle phenotype as McArdle patients, including undetectable myophosphorylase protein and activity in skeletal muscle, massive muscle glycogen accumulation, hyperCKaemia and very poor exercise performance (Nogales-Gadea, 2012).
• PP5: Variant 11-64759751-G-A is Pathogenic according to our data. Variant chr11-64759751-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.00295 (4312/1461882) while in subpopulation NFE AF = 0.00366 (4073/1112008). AF 95% confidence interval is 0.00357. There are 10 homozygotes in GnomAdExome4. There are 2030 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005609.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	NM_005609.4	MANE Select	c.148C>T	p.Arg50*	stop_gained	Exon 1 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.148C>T	p.Arg50*	stop_gained	Exon 1 of 18	NP_001158188.1	P11217-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYGM	ENST00000164139.4	TSL:1 MANE Select	c.148C>T	p.Arg50*	stop_gained	Exon 1 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.148C>T	p.Arg50*	stop_gained	Exon 1 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.148C>T	p.Arg50*	stop_gained	Exon 1 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152240 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000675

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00145 AC: 365 AN: 251452 AF XY: 0.00145

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00245

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00295 AC: 4312 AN: 1461882 Hom.: 10 Cov.: 31 AF XY: 0.00279 AC XY: 2030 AN XY: 727240

African (AFR) AF: 0.000418 AC: 14 AN: 33480

American (AMR) AF: 0.00125 AC: 56 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00366 AC: 4073 AN: 1112008

Other (OTH) AF: 0.00225 AC: 136 AN: 60394

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152358 Hom.: 2 Cov.: 33 AF XY: 0.00166 AC XY: 124 AN XY: 74500

African (AFR) AF: 0.000673 AC: 28 AN: 41598

American (AMR) AF: 0.00131 AC: 20 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00220 Hom.: 3

Bravo AF: 0.00189

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00137 AC: 166

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
22	-	-	Glycogen storage disease, type V (24)
10	-	-	not provided (10)
1	-	-	Hereditary skeletal muscle disorder (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	See cases (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.0019
FATHMM_MKL	Uncertain	0.76	D
PhyloP100		2.6
Vest4		0.64
GERP RS		2.4
PromoterAI		-0.029	Neutral
Mutation Taster		=0/200	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: rs116987552; hg19: chr11-64527223;