rs527236147

Variant names:

• chr11-64750422-TGAA-T
• rs527236147
• NM_005609.4:c.2128_2130delTTC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM4_Supporting PP5_Very_Strong

The NM_005609.4(PYGM):​c.2128_2130delTTC​(p.Phe710del) variant causes a conservative 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 conservative_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 9.28
• Publications: 8 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 11 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, 7 uncertain in NM_005609.4
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 139609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4	c.2128_2130delTTC	p.Phe710del	conservative_inframe_deletion	Exon 17 of 20	ENST00000164139.4	NP_005600.1
PYGM	NM_001164716.1	c.1864_1866delTTC	p.Phe622del	conservative_inframe_deletion	Exon 15 of 18		NP_001158188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4	c.2128_2130delTTC	p.Phe710del	conservative_inframe_deletion	Exon 17 of 20	1	NM_005609.4	ENSP00000164139.3
PYGM	ENST00000377432.7	c.1864_1866delTTC	p.Phe622del	conservative_inframe_deletion	Exon 15 of 18	2		ENSP00000366650.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251490 AF XY: 0.0000147

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000756 AC: 30 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:8 Other:1

Jun 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2014

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Aug 18, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 31, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 31, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 10, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=63/37	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs527236147; hg19: chr11-64517894;