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NM_002103.5(GYS1):c.678+1G>A AND Glycogen storage disease due to muscle and heart glycogen synthase deficiency

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Mar 27, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001061520.11

Allele description [Variation Report for NM_002103.5(GYS1):c.678+1G>A]

NM_002103.5(GYS1):c.678+1G>A

Gene:
GYS1:glycogen synthase 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
19q13.33
Genomic location:
Preferred name:
NM_002103.5(GYS1):c.678+1G>A
HGVS:
  • NC_000019.10:g.48985849C>T
  • NG_012923.1:g.12505G>A
  • NM_001161587.2:c.486+1G>A
  • NM_002103.5:c.678+1G>AMANE SELECT
  • NC_000019.9:g.49489106C>T
  • NM_002103.4:c.678+1G>A
Links:
dbSNP: rs755305465
NCBI 1000 Genomes Browser:
rs755305465
Molecular consequence:
  • NM_001161587.2:c.486+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_002103.5:c.678+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:
Glycogen storage disease due to muscle and heart glycogen synthase deficiency
Synonyms:
GSD 0b; Glycogen storage disease 0, muscle; Muscle glycogen synthase deficiency
Identifiers:
MONDO: MONDO:0012693; MedGen: C1969054; Orphanet: 137625; OMIM: 611556

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001226265Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Nov 14, 2022)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002024935Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Mar 19, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV003922860Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Likely pathogenic
(Mar 27, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]
PMID:
16199547
PMCID:
PMC1735933

Cardiomyopathy and exercise intolerance in muscle glycogen storage disease 0.

Kollberg G, Tulinius M, Gilljam T, Ostman-Smith I, Forsander G, Jotorp P, Oldfors A, Holme E.

N Engl J Med. 2007 Oct 11;357(15):1507-14.

PubMed [citation]
PMID:
17928598
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001226265.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 856123). This variant has not been reported in the literature in individuals affected with GYS1-related conditions. This variant is present in population databases (rs755305465, gnomAD 0.01%). This sequence change affects a donor splice site in intron 4 of the GYS1 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 GYS1 are known to be pathogenic (PMID: 17928598, 19699667).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002024935.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922860.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: GYS1 c.678+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. The TraP (transcript-inferred pathogenicity) in silico prediction tool scores the variant as probably pathogenic. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251360 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.678+1G>A in individuals affected with GYS1-related disorders and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant affecting the same nucleotide, c.678+1G>C, has been reported in a homozygous individual with adult-onset myopathy without cardiomyopathy (PMID: 35641353). Two ClinVar submitters (evaluation after 2014) have cited the variant, and both submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024