ClinVar Miner

Submissions for variant NM_005609.4(PYGM):c.1768+1G>A

gnomAD frequency: 0.00007  dbSNP: rs771427957
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000423322 SCV000226114 pathogenic not provided 2014-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000423322 SCV000521109 pathogenic not provided 2023-06-29 criteria provided, single submitter clinical testing Previously published in association with McArdle disease (Tsujino et al., 1994; Rubio et al., 2007).; Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate that the variant resulted in a truncated fragment that harbored a 67 base pair deletion (Tsujino et al., 1994); This variant is associated with the following publications: (PMID: 25914343, 26913921, 17221871, 34534370, 30415384, 31589614, 34276053, 8279469)
Ambry Genetics RCV000624349 SCV000740890 pathogenic Inborn genetic diseases 2015-05-19 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763265 SCV000893904 pathogenic Glycogen storage disease, type V 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000763265 SCV001392316 pathogenic Glycogen storage disease, type V 2024-04-09 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 14 of the PYGM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PYGM are known to be pathogenic (PMID: 8316268, 16786513). This variant is present in population databases (rs771427957, gnomAD 0.02%). Disruption of this splice site has been observed in individuals with glycogen storage disease type V (GSD V), also known as McArdle disease (PMID: 8279469, 22250184, 30415384). ClinVar contains an entry for this variant (Variation ID: 194389). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000763265 SCV002019579 pathogenic Glycogen storage disease, type V 2021-09-14 criteria provided, single submitter clinical testing
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India RCV000763265 SCV002053924 likely pathogenic Glycogen storage disease, type V criteria provided, single submitter research
Lifecell International Pvt. Ltd RCV000763265 SCV003921114 pathogenic Glycogen storage disease, type V criteria provided, single submitter clinical testing A Heterozygous Splice site donor variant c.1768+1G>A in Exon 14 of the PYGM gene that results in the amino acid substitution was identified. The observed variant has allele frequency of 0.00002/0.00006% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic/LikelyPathogenic (ClinVar ID: 194389). This sequence change affects a donor splice site in intron 14 of the PYGM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (Baralle D et al., 2005). Disruption of this splice site has been observed in individuals with glycogen storage disease type V (GSD V), also known as McArdle disease (Lucia A et al., 2012 and Lorenzoni PJ et al., 2020). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Baylor Genetics RCV000763265 SCV004207237 pathogenic Glycogen storage disease, type V 2024-02-21 criteria provided, single submitter clinical testing
OMIM RCV000763265 SCV000022553 pathogenic Glycogen storage disease, type V 1999-06-01 no assertion criteria provided literature only
Natera, Inc. RCV000763265 SCV001461275 pathogenic Glycogen storage disease, type V 2020-09-16 no assertion criteria provided clinical testing

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