NM_005609.4:c.148C>T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 16P and 1B. PVS1PP5_Very_StrongBS1_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 (★★). 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

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:34O:1

Conservation

PhyloP100: 2.56
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-64759751-G-A is Pathogenic according to our data. Variant chr11-64759751-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2298.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-64759751-G-A is described in Lovd as [Pathogenic]. Variant chr11-64759751-G-A is described in Lovd as [Pathogenic]. Variant chr11-64759751-G-A is described in Lovd as [Likely_pathogenic].
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 2030 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PYGMNM_005609.4 linkc.148C>T p.Arg50* stop_gained Exon 1 of 20 ENST00000164139.4 NP_005600.1 P11217-1
PYGMNM_001164716.1 linkc.148C>T p.Arg50* stop_gained Exon 1 of 18 NP_001158188.1 P11217-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PYGMENST00000164139.4 linkc.148C>T p.Arg50* stop_gained Exon 1 of 20 1 NM_005609.4 ENSP00000164139.3 P11217-1
PYGMENST00000377432.7 linkc.148C>T p.Arg50* stop_gained Exon 1 of 18 2 ENSP00000366650.3 P11217-2

Frequencies

GnomAD3 genomes
AF:
0.00176
AC:
268
AN:
152240
Hom.:
2
Cov.:
33
show subpopulations
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
GnomAD3 exomes
AF:
0.00145
AC:
365
AN:
251452
Hom.:
0
AF XY:
0.00145
AC XY:
197
AN XY:
135906
show subpopulations
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 SAS exome
AF:
0.0000327
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
Gnomad4 AMR exome
AF:
0.00125
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000580
Gnomad4 NFE exome
AF:
0.00366
Gnomad4 OTH exome
AF:
0.00225
GnomAD4 genome
AF:
0.00176
AC:
268
AN:
152358
Hom.:
2
Cov.:
33
AF XY:
0.00166
AC XY:
124
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.000673
Gnomad4 AMR
AF:
0.00131
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.000376
Gnomad4 NFE
AF:
0.00312
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.00221
Hom.:
0
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

Significance: Pathogenic
Submissions summary: Pathogenic:34Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Glycogen storage disease, type V Pathogenic:21Other:1
Apr 22, 2022
Molecular Genetics, Royal Melbourne Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature termination codon at position 50 in exon 1 (of 20) of PYGM, p.(Arg50*). This alteration is expected to result in nonsense-mediated decay in a gene where loss of function is a known mechanism of disease. The variant is present in a large population cohort at a frequency of 0.15% (rs116987552, 424/282,854 alleles, 0 homozygotes in gnomAD v2.1), and is the most common pathogenic variant associated with glycogen storage disease type V (also known as McArdle disease) in the European population. The variant has been identified as homozygous and compound heterozygous with a second pathogenic allele in many cases with a clinical diagnosis of McArdle disease (PMID: 8316268). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_VeryStrong. -

Feb 01, 2023
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PYGM c.148C>T (p.Arg50Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg50Ter variant is the most commonly identified variant in patients with glycogen storage disease type V, also known as McArdle disease, in the majority of populations studied (Martin et al. 2006; Nogales-Gadea et al. 2015). Across a selection of the available literature, the p.Arg50Ter variant is detected with an allele frequency ranging from 43%-78% in the respective patient cohorts (Tsujino et al. 1993; Bruno et al. 2006; Aquaron et al. 2007; Deschauer et al. 2007; Vieitez et al. 2011; Gurgel-Giannetti et al. 2013). The variant was absent from 96 healthy individuals but is reported at a frequency of 0.00314 in the European American population of the Exome Sequencing Project. A knock-in mouse model homozygous for the p.Arg50Ter variant displays a McArdle disease-like phenotype (Nogales-Gadea et al. 2012). Based on the collective evidence, the p.Arg50Ter 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. -

Jun 11, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PYGM c.148C>T; p.Arg50Ter variant (rs116987552, ClinVar Variation ID: 2298), also known as R49X in traditional nomenclature, is reported in the literature in individuals affected with McArdle disease and is the most common pathogenic variant in individuals of European descent (selected references: Gurgel-Giannetti 2013, Martin 2006, Tsujino 1993). This variant is found in the general population with an overall allele frequency of 0.15% (424/282854 alleles) in the Genome Aggregation Database (v2.1.1). This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, a knock-in mouse model demonstrates a McArdle disease like phenotype. (Nogales-Gadea 2012). Based on available information, this variant is considered to be pathogenic. References: Gurgel-Giannetti J et al. Clinical and molecular characterization of McArdle's disease in Brazilian patients. Neuromolecular Med. 2013 Sep;15(3):470-5. PMID: 23653251. Martin MA et al. Glycogen Storage Disease Type V. 2006 Apr 19 [updated 2019 Jun 20]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301518. Nogales-Gadea G et al. Knock-in mice for the R50X mutation in the PYGM gene present with McArdle disease. Brain. 2012 Jul;135(Pt 7):2048-57. PMID: 22730558. Tsujino S et al. Molecular genetic heterogeneity of myophosphorylase deficiency (McArdle's disease). N Engl J Med. 1993 Jul 22;329(4):241-5. PMID: 8316268. -

Jun 22, 2023
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.148C>T (p.Arg50X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 0.0015 in 251452 control chromosomes in gnomAD. This frequency is not significantly higher than estimated for a pathogenic variant in PYGM causing Glycogen Storage Disease Type V, also known as McArdle disease, (0.0015 vs 0.0035), allowing no conclusion about variant significance. c.148C>T has been reported in the literature in individuals affected with Glycogen Storage Disease Type V (example: Cerino_2022). These data indicate that the variant is very likely associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 35741838). Twenty submitters have cited clinical-significance assessments (all pathogenic) for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 05, 2024
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 16, 2020
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 08, 2016
Counsyl
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 13, 2021
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genomics England Pilot Project, Genomics England
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 06, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The PYGM c.148C>T variant is classified as Pathogenic (PVS1, PS3, PS4, PM3) The PYGM c.148C>T variant is a single nucleotide change which is predicted to result in premature termination of the protein product at codon 50 (PVS1). The variant has been reported in probands with a clinical presentation of OMIM:232600 ( Reported multiple times in OMIM:608455 ) (PS4). Well-established functional studies show a deleterious 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). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Identified in another case as compound het with a second pathogenic variant in PYGM (c.613G>A;p.Gly205Ser). This variant was shown to be maternally inherited and the c.613G>A variant is paternally inherited in that case. The variant has been reported in dbSNP (rs116987552) and in the HGMD database: CM930629. It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2298). -

Jan 12, 2016
Molecular Diagnostics Lab, Nemours Children's Health, Delaware
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

May 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 05, 2022
DASA
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.148C>T;p.(Arg50*) variant creates a premature translational stop signal in the PYGM gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 2298; PMID: 20301518; PMID: 23653251; PMID: 17324573; PMID: 12929201; PMID:20301518) - PS4. The variant is present at low allele frequencies population databases (rs116987552 – gnomAD 0.01499%; ABraOM 0.001708 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg50*) was detected in trans with a pathogenic variant (PMID: 23653251; PMID: 17324573) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Jun 27, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg50X variant in PYGM is a known pathogenic variant that has been report ed in at least 50 homozygotes and 29 compound heterozygous with glycogen storage disease type V (GSDV), also known as McArdle disease, and segregated with disea se in 5 affected siblings from 4 families (Tsujino 1993, Gurgel-Giannetti 2013, deLuna 2014, and Hongrel 2015). Mouse models demonstrate that this variant cause s glycogen storage disease type V (Nogales-Gadea 2012 and Brull 2015). It has al so been reported in ClinVar (Variation ID 2298) by multiple laboratories as path ogenic and has been identified in 0.20% (318/126684) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be co nsistent with a recessive carrier frequency. In summary, this variant meets crit eria to be classified as pathogenic for autosomal recessive GSDV based upon case observations, segregation studies, and animal models. ACMG/AMP Criteria applied : PVS1, PM3_Very Strong, PS3, PP1_Strong. -

-
GeneReviews
Significance: not provided
Review Status: no classification provided
Collection Method: literature only

- -

Jan 28, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg50*) in the PYGM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs116987552, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with McArdle disease (PMID: 8316268, 16786513, 21802952, 22250184, 23653251). ClinVar contains an entry for this variant (Variation ID: 2298). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PYGM function (PMID: 22730558). For these reasons, this variant has been classified as Pathogenic. -

Oct 19, 2020
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with McArdle disease (MIM#232600). (I) 0106 - This gene is associated with autosomal recessive disease. However, a single family has been reported for an autosomal dominant glycogen storage disorder (PMID: 32386344). (I) 0115 - Variants in this gene are known to have variable expressivity. Some affected individuals have minimal symptoms with essentially no limitations in activities of daily living. This may be attributed to variable physical activity habits (Gene Reviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 253 heterozygotes, 1 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Several NMD-predicted variants have been reported in patients with McArdle disease (MIM#232600) (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in several McArdle disease (MIM#232600) patients in both homozygous and compound heterozygous states (ClinVar; PMID: 29143597). (SP) 1205 - This variant has been shown to be maternally inherited (VCGS #20G001969). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 30, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 19, 2023
Institute of Immunology and Genetics Kaiserslautern
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG Criteria: PVS1, PS3, PS4, PM3, PP1, PP5; Variant was found in compound heterozygous state with NM_005609.4:c.1477del. -

Jul 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Oct 18, 2021
Columbia University Laboratory of Personalized Genomic Medicine, Columbia University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The c.148C>T (p.Arg50Ter) variant in PYGM identified in this individual is one of the most common, well established, pathogenic variants described in PYGM (Nogales-Gadea et al., 2015). To date, this variant has eleven independent pathogenic curations in ClinVar (VarID:2298). 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). -

not provided Pathogenic:10
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PYGM p.R50* variant is a well-known pathogenic variant known to cause McArdle disease and is the most common pathogenic variant in individuals of European and US descent (Martin_2019_PMID:20301518). The variant was identified in dbSNP (ID: rs116987552), ClinVar (classified as pathogenic by Counsyl, Ambry Genetics, GeneDx, EGL Genetic Diagnostics, Invitae, Laboratory for Molecular Medicine, Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Fulgent Genetics, Illumina and Molecular Diagnostics Lab, Nemours Alfred I. duPont Hospital for Children) and LOVD 3.0 (classified as pathogenic). The variant was identified in control databases in 424 of 282854 chromosomes at a frequency of 0.001499 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 325 of 129154 chromosomes (freq: 0.002516), Other in 18 of 7226 chromosomes (freq: 0.002491), Latino in 48 of 35440 chromosomes (freq: 0.001354), African in 18 of 24972 chromosomes (freq: 0.000721), European (Finnish) in 12 of 25122 chromosomes (freq: 0.000478), Ashkenazi Jewish in 1 of 10370 chromosomes (freq: 0.000096), East Asian in 1 of 19954 chromosomes (freq: 0.00005), and South Asian in 1 of 30616 chromosomes (freq: 0.000033). The c.148C>T variant leads to a premature stop codon at position 50 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PYGM gene are an established mechanism of disease in McArdle disease and is the type of variant known to cause the disorder in the homozygous or compound heterozygous state. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Mouse models with the p.R50* variant display a McArdle disease phenotype (Nogales-Gadea_2012_PMID:22730558; Brull_2015_PMID: 25873271). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 06, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 29, 2015
Clinical Genetics and Genomics, Karolinska University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 13, 2023
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PYGM: PM3:Very Strong, PVS1, PM2, PS3:Supporting -

Jul 16, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 31, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25873271, 31980526, 32124677, 31517061, 29961518, 30609409, 30316539, 30415384, 29382405, 22995991, 22344438, 20981092, 18667317, 10918252, 9120482, 27899787, 27300253, 26670295, 27031745, 22730558, 27030740, 22818872, 8316268, 17404776, 25741863, 26240973, 25240406, 25914343, 23653251) -

Inborn genetic diseases Pathogenic:1
Sep 07, 2014
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

See cases Pathogenic:1
Jun 24, 2020
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

ACMG classification criteria: PVS1, PS3, PS4, PM3, PP1 -

Tip-toe gait Pathogenic:1
Dec 19, 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. -

Computational scores

Source: dbNSFP v4.3

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
Vest4
0.64
GERP RS
2.4

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.

Other links and lift over

dbSNP: rs116987552; hg19: chr11-64527223; API