NM_002103.5(GYS1):c.1318T>C (p.Phe440Leu) AND Glycogen storage disease due to muscle and heart glycogen synthase deficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 20, 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:: RCV002532403.5

Allele description [Variation Report for NM_002103.5(GYS1):c.1318T>C (p.Phe440Leu)]

NM_002103.5(GYS1):c.1318T>C (p.Phe440Leu)

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.1318T>C (p.Phe440Leu)

HGVS:

NC_000019.10:g.48974724A>G
NG_012923.1:g.23630T>C
NM_001161587.2:c.1126T>C
NM_002103.5:c.1318T>CMANE SELECT
NP_001155059.1:p.Phe376Leu
NP_002094.2:p.Phe440Leu
NC_000019.9:g.49477981A>G
NR_027763.2:n.1333T>C

Protein change:

F376L

Links:

dbSNP: rs756191455

NCBI 1000 Genomes Browser:

rs756191455

Molecular consequence:

NM_001161587.2:c.1126T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_002103.5:c.1318T>C - missense variant - [Sequence Ontology: SO:0001583]
NR_027763.2:n.1333T>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003469025	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 25, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003810637	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jan 20, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003469025

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 25, 2022)

germline

clinical testing

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

SCV003810637

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jan 20, 2023)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003469025.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 440 of the GYS1 protein (p.Phe440Leu). This variant is present in population databases (rs756191455, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with GYS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 498163). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003810637.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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