rs148839812

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005609.4(PYGM):c.160T>G(p.Phe54Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

PYGM
NM_005609.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:12

Conservation

PhyloP100: 9.07

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGM	NM_005609.4 link	c.160T>G	p.Phe54Val	missense_variant	Exon 1 of 20	ENST00000164139.4	NP_005600.1	P11217-1
PYGM	NM_001164716.1 link	c.160T>G	p.Phe54Val	missense_variant	Exon 1 of 18		NP_001158188.1	P11217-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGM	ENST00000164139.4 link	c.160T>G	p.Phe54Val	missense_variant	Exon 1 of 20	1	NM_005609.4	ENSP00000164139.3		P11217-1
PYGM	ENST00000377432.7 link	c.160T>G	p.Phe54Val	missense_variant	Exon 1 of 18	2		ENSP00000366650.3		P11217-2

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000310

AC:

AN:

251470

Hom.:

AF XY:

0.000375

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.000624

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000362

AC:

529

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000385

AC XY:

280

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.000450

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000447

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000431

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000824

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000931

AC:

ExAC

AF:

0.000338

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease, type V

Uncertain:6

Jun 13, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2024

Department of Human Genetics, Hannover Medical School

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG: PP3 -

Oct 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 54 of the PYGM protein (p.Phe54Val). This variant is present in population databases (rs148839812, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with PYGM-related conditions. ClinVar contains an entry for this variant (Variation ID: 580278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PYGM protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jan 24, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 17, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PYGM c.160T>G; p.Phe54Val variant (rs148839812), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 580278). This variant is found in the non-Finnish European population with an allele frequency of 0.08% (99/129170 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.736). Due to limited information, the clinical significance of this variant is uncertain at this time. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Mar 22, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2 -

Sep 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Sep 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tip-toe gait

Pathogenic:1

Sep 30, 2022

Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

Toe Walking has various causes, ranging from idiopathic or habitual reasons to an underlying neuromuscular disease. The most observed form of toe walking is idiopathic toe walking (ITW) - a diagnosis of exclusion. ITW occurs in about 5% of children after their second birthday and is a common problem in pediatric orthopedics. In about 70% of these cases, there is spontaneous remission within six months of the onset of ITW. If the toe walk persists, one can assume the presence of a non-idiopathic form of toe walk (n-ITW). In n-ITW, the causes of the abnormal gait are neurological or myogenic. Differential diagnoses such as infantile cerebral palsy, muscular dystrophy, spinal amyotrophy and hereditary motor-sensory neuropathy as well as rare metabolic disorders of the musculature must be considered (Pomarino et al., 2018). In our clinical ITW consultation, we screen children with n-ITW for a genetic form of tiptoe gait using next generation sequencing for gene variants in 49 genes. These are genes in which gene variants can lead to neuromuscular diseases in which an association with toe-tapping gait has been reported or can be suspected due to patients’ clinical symptoms. To the best of our knowledge, this is the first study in which several patients with toe walking displayed heterozygosity for pathogenic or likely pathogenic PYGM mutations and mild symptoms of the metabolic muscle disease McArdle. The findings of our research are in line with recently published observations in heterozygous family members patients with McArdle disease. We should mention that some of the patients in our cohort harbored heterozygous variants in other genes of our gene panel. However, the numbers in this study were too small to workout any resulting combined genetic effects. It is concluded that genetic conditions can contribute to the development of toe walking. Apparently, even a slight genetic weakening of the muscles can lead to changes to the gait pattern. Future studies must show how the pathomechanism can be explained for the PYGM variants and whether there are new therapeutic approaches to be developed based on this research. -

not specified

Uncertain:1

Aug 09, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PYGM c.160T>G (p.Phe54Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251470 control chromosomes, predominantly at a frequency of 0.00062 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00031 vs 0.0035), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.160T>G in individuals affected with Glycogen Storage Disease, Type V and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 580278). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Apr 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.160T>G (p.F54V) alteration is located in exon 1 (coding exon 1) of the PYGM gene. This alteration results from a T to G substitution at nucleotide position 160, causing the phenylalanine (F) at amino acid position 54 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

High myopia

Uncertain:1

Dec 17, 2018

Institute of Human Genetics, Polish Academy of Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.098

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.38

.;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.086

MetaRNN

Uncertain

0.50

D;D

MetaSVM

Uncertain

0.046

MutationAssessor

Uncertain

2.1

M;M

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.4

D;D

REVEL

Pathogenic

0.74

Sift

Benign

0.20

T;T

Sift4G

Benign

0.58

T;T

Polyphen

0.041

.;B

Vest4

0.86

MVP

0.90

MPC

0.97

ClinPred

0.21

GERP RS

5.6

Varity_R

0.56

gMVP

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over