rs527236147

chr11-64750422-TGAA-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_005609.4(PYGM):c.2128_2130del(p.Phe710del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PYGM NM_005609.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 9.28

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 13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005609.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_005609.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-64750422-TGAA-T is Pathogenic according to our data. Variant chr11-64750422-TGAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 139609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64750422-TGAA-T is described in Lovd as [Likely_pathogenic]. Variant chr11-64750422-TGAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGM	NM_005609.4	c.2128_2130del	p.Phe710del	inframe_deletion	17/20	ENST00000164139.4
PYGM	NM_001164716.1	c.1864_1866del	p.Phe622del	inframe_deletion	15/18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGM	ENST00000164139.4	c.2128_2130del	p.Phe710del	inframe_deletion	17/20	1	NM_005609.4	P1
PYGM	ENST00000377432.7	c.1864_1866del	p.Phe622del	inframe_deletion	15/18	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251490 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461888 Hom.: 0 AF XY: 0.0000206 AC XY: 15 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:7 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 18, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2022	Variant summary: PYGM c.2128_2130delTTC (p.Phe710del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 1.2e-05 in 251490 control chromosomes. c.2128_2130delTTC has been reported in the literature in multiple individuals affected with Glycogen Storage Disease, Type V (example, Sugie_1995, Park_2014, Ugur_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Sugie_1995). The most pronounced variant effect results in <5% of normal muscle myophosphorylase enzyme activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 31, 2020	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	This variant, c.2128_2130del, results in the deletion of 1 amino acid(s) of the PYGM protein (p.Phe710del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs527236147, gnomAD 0.02%). This variant has been observed in individuals with PYGM-related conditions (PMID: 7664468, 7951211, 8279469, 25045239, 28967462, 31320798). It has also been observed to segregate with disease in related individuals. This variant is also known as Phe708del and Phe709del. ClinVar contains an entry for this variant (Variation ID: 139609). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 20, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 10, 2017	The PYGM c.2128_2130delTTC (p.Phe710del) variant result in an inframe deletion. Across a selection of the available literature, the p.Phe710del variant has been identified in a total of 13 individuals with glycogen storage disease type V including 11 in a homozygous state and two in a compound heterozygous state (Tsujino et al. 1994; Tsujino et al. 1994; Sugie et al. 1995; Park et al. 2014; Inal-Gültekin et al. 2017). Six of the homozygous patients were pairs of siblings. The second variant in the compound heterozygous patients was either a frameshift resulting in premature termination or an unidentified variant that resulted in weak gene expression. The p.Phe710del variant segregated with disease in one family that consisted of two affected homozygous siblings and two unaffected heterozygous carrier parents (Tsujino et al. 1994a). The p.Phe710del variant was absent from 163 controls (Tsujino et al. 1994a; Sugie et al. 1995; Inal-Gültekin et al. 2017) and is reported at a frequency of 0.00023 in the East Asian population of the Genome Aggregation Database. Based on the collective evidence, the p.Phe710del variant is classified as pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Jul 10, 2014	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs527236147; hg19: chr11-64517894;