rs1057516612

Variant names:

• chr11-64752493-CTCC-TCA
• rs1057516612
• NM_005609.4:c.1527_1530delGGAGinsTGA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005609.4(PYGM):​c.1527_1530delGGAGinsTGA​(p.Glu510ThrfsTer28) variant causes a frameshift, stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G509G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYGM NM_005609.4 frameshift, stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.93
• Publications: 3 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: Genomics England PanelApp, ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-64752493-CTCC-TCA is Pathogenic according to our data. Variant chr11-64752493-CTCC-TCA is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 370590.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1527_1530delGGAGinsTGA	p.Glu510ThrfsTer28	frameshift stop_gained	Exon 13 of 20	NP_005600.1	P11217-1
	PYGM	NM_001164716.1		c.1263_1266delGGAGinsTGA	p.Glu422ThrfsTer28	frameshift stop_gained	Exon 11 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.1527_1530delGGAGinsTGA	p.Glu510ThrfsTer28	frameshift stop_gained	Exon 13 of 20	ENSP00000164139.3	P11217-1
	PYGM	ENST00000967737.1		c.1626_1629delGGAGinsTGA	p.Glu543ThrfsTer28	frameshift stop_gained	Exon 14 of 21	ENSP00000637796.1
	PYGM	ENST00000938870.1		c.1443_1446delGGAGinsTGA	p.Glu482ThrfsTer28	frameshift stop_gained	Exon 13 of 20	ENSP00000608929.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Glycogen storage disease, type V (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1057516612;

hg19: chr11-64519965;