rs116135678
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_005609.4(PYGM):c.1094C>T(p.Ala365Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000875 in 1,601,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A365A) has been classified as Likely benign.
Frequency
Consequence
NM_005609.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYGM | NM_005609.4 | c.1094C>T | p.Ala365Val | missense_variant, splice_region_variant | 10/20 | ENST00000164139.4 | |
PYGM | NM_001164716.1 | c.830C>T | p.Ala277Val | missense_variant, splice_region_variant | 8/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYGM | ENST00000164139.4 | c.1094C>T | p.Ala365Val | missense_variant, splice_region_variant | 10/20 | 1 | NM_005609.4 | P1 | |
PYGM | ENST00000377432.7 | c.830C>T | p.Ala277Val | missense_variant, splice_region_variant | 8/18 | 2 | |||
PYGM | ENST00000460413.1 | n.171C>T | splice_region_variant, non_coding_transcript_exon_variant | 2/3 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.000736 AC: 112AN: 152184Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000711 AC: 160AN: 224920Hom.: 0 AF XY: 0.000797 AC XY: 97AN XY: 121746
GnomAD4 exome AF: 0.000890 AC: 1290AN: 1448742Hom.: 1 Cov.: 37 AF XY: 0.000872 AC XY: 627AN XY: 719410
GnomAD4 genome ? AF: 0.000729 AC: 111AN: 152302Hom.: 0 Cov.: 31 AF XY: 0.000591 AC XY: 44AN XY: 74482
ClinVar
Submissions by phenotype
Glycogen storage disease, type V Pathogenic:5Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 08, 2023 | - - |
Likely pathogenic, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | May 27, 2015 | The variant (c.1094C>T; p.A365V) is considered to be likely pathogenic because it has been reported in several patients with biochemically proven McArdle disease across multiple cohorts and has been modeled to occur in a very densely packed and critical region of the gene for glycogen binding (PMID: 21802952; 17630210; 17221871). It occurs at low frequencies in ExAC (allele frequency of 65 out of 62854 alleles, 0.1%). The variant occurs in highly conserved amino acid and nucleotide positions but not in a functional domain. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 14, 2023 | Variant summary: PYGM c.1094C>T (p.Ala365Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a cryptic 5 donor site. One predicts the variant strengthens a cryptic 5 donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00071 in 224920 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PYGM causing Glycogen Storage Disease, Type V (0.00071 vs 0.0035), allowing no conclusion about variant significance. In a conservative assessment of the literature, c.1094C>T has been reported in compound heterozygosity in individuals affected with Glycogen Storage Disease, Type V (example, Vieitez_2011, Rubio_2007, Bruno_2006, Lucia_2012, Inal-Gultekin_2017, Santalla_2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 16786513, 25741863, 28967462, 22250184, 17221871, 29143597, 21802952). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=5), likely pathogenic (n=5) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 365 of the PYGM protein (p.Ala365Val). This variant is present in population databases (rs116135678, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with McArdle disease (PMID: 17221871, 29143597; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203394). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PYGM c.1094C>T (p.Arg365Val) missense variant has been reported in four studies in which it is found in a compound heterozygous state in five patients with glycogen storage disease type V, and in two additional patient alleles of unknown zygosity (Bruno et al. 2006; Rubio et al. 2007; Rubio et al. 2007; Lucia et al. 2012). The p.Arg365Val variant was absent from 246 controls but is reported at a frequency of 0.00851 in the other population of the Exome Aggregation Consortium. The Arg365 variant is located in a highly conserved region of the protein (Rubio et al. 2007). Based on the evidence the p.Arg365Val variant is classified as likely pathogenic for glycogen storage disease type V. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Ala365Val variant in PYGM has been reported, in the compound heterozygous state, in over 5 individuals with Glycogen Storage Disease, Type V (McArdle disease ) (Vieitez 2011 PMID: 21802952, Rubio 2007 PMID: 17630210, Bruno 2006 PMID: 16786513, Lucia 2012 PMID: 22250184, Inal-Gultekin 2017 PMID: 28967462, Santalla 2017 PMID: 29143597). This variant has been reported in ClinVar (Variation ID 203394) and it has been identified in 71/68026 European chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Glycogen Storage Disease, Type V. ACMG/AMP Criteria applied: PM3_Very Strong, PP3. - |
not provided Pathogenic:2Uncertain:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 10, 2020 | PS4_moderate, PM2, PP3, PP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PYGM: PM2, PM3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21802952, 20981092, 16786513, 17221871, 17630210, 29143597, 22250184, 34426522, 25741863, 29907799, 28967462, 30011114) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 26, 2015 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PYGM p.Ala277Val variant was identified in 5 of 666 proband chromosomes (frequency: 0.0075) from individuals with McArdle disease (Santalla_2017_PMID:29143597). The variant was identified in dbSNP (ID: rs116135678) and ClinVar (classified as uncertain significance by Invitae and EGL Genetics and as likely pathogenic by Illumina and Division of Human Genetics, Children's Hospital of Philadelphia). The variant was also identified in control databases in 172 of 256272 chromosomes at a frequency of 0.0006712 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 10 of 9824 chromosomes (freq: 0.001018), European (non-Finnish) in 115 of 115330 chromosomes (freq: 0.000997), Latino in 30 of 32778 chromosomes (freq: 0.000915), Other in 6 of 6708 chromosomes (freq: 0.000895), African in 5 of 22454 chromosomes (freq: 0.000223), South Asian in 4 of 28262 chromosomes (freq: 0.000142), East Asian in 1 of 18386 chromosomes (freq: 0.000054), and European (Finnish) in 1 of 22530 chromosomes (freq: 0.000044). The p.Ala277 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence however three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Tip-toe gait Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino | Jan 11, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at