ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.1094C>T (p.Ala365Val) (rs116135678)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000723508 SCV000331200 uncertain significance not provided 2015-10-26 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000185576 SCV000373025 likely pathogenic Glycogen storage disease, type V 2017-04-27 criteria provided, single submitter clinical testing 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.
Invitae RCV000185576 SCV000830856 uncertain significance Glycogen storage disease, type V 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 365 of the PYGM protein (p.Ala365Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs116135678, ExAC 0.2%). This variant has been observed in several individuals affected with McArdle disease (PMID: 29143597, 17221871). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "C0"). 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000723508 SCV001247784 likely pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000185576 SCV001519532 likely pathogenic Glycogen storage disease, type V 2021-03-09 criteria provided, single submitter clinical testing 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. The variant allele was found at a frequency of 0.00071 in 224920 control chromosomes. 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely pathogenic, n=3; VUS, n=3). Some submitters reporting a VUS classification cite a subset of overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000723508 SCV001714985 uncertain significance not provided 2020-02-10 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000185576 SCV001737323 uncertain significance Glycogen storage disease, type V 2021-06-10 criteria provided, single submitter clinical testing
Division of Human Genetics,Children's Hospital of Philadelphia RCV000185576 SCV000238476 likely pathogenic Glycogen storage disease, type V 2015-05-27 no assertion criteria provided research 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.
Natera, Inc. RCV000185576 SCV001461285 uncertain significance Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000723508 SCV001552232 uncertain significance not provided no assertion criteria provided clinical testing 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.

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