12-21568952-G-A

Position:

chr12-21568952-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_021957.4(GYS2):c.736C>T(p.Arg246Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000252 in 1,613,202 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

GYS2
NM_021957.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 3.62

Variant links:

Genes affected

GYS2 (HGNC:4707): (glycogen synthase 2) The protein encoded by this gene, liver glycogen synthase, catalyzes the rate-limiting step in the synthesis of glycogen - the transfer of a glucose molecule from UDP-glucose to a terminal branch of the glycogen molecule. Mutations in this gene cause glycogen storage disease type 0 (GSD-0) - a rare type of early childhood fasting hypoglycemia with decreased liver glycogen content. [provided by RefSeq, Dec 2009]

GYS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 12-21568952-G-A is Pathogenic according to our data. Variant chr12-21568952-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GYS2	NM_021957.4 linkuse as main transcript	c.736C>T	p.Arg246Ter	stop_gained	5/16	ENST00000261195.3
GYS2	XM_024448960.2 linkuse as main transcript	c.736C>T	p.Arg246Ter	stop_gained	5/17
GYS2	XM_006719063.4 linkuse as main transcript	c.505C>T	p.Arg169Ter	stop_gained	4/15
GYS2	XM_017019245.3 linkuse as main transcript	c.736C>T	p.Arg246Ter	stop_gained	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS2	ENST00000261195.3 linkuse as main transcript	c.736C>T	p.Arg246Ter	stop_gained	5/16	1	NM_021957.4	P1

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000382

AC:

AN:

251426

Hom.:

AF XY:

0.000500

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00209

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000265

AC:

387

AN:

1460936

Hom.:

Cov.:

AF XY:

0.000312

AC XY:

227

AN XY:

726844

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00206

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000131

AC:

AN:

152266

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000126

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000395

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disorder due to hepatic glycogen synthase deficiency

Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2023	Variant summary: GYS2 c.736C>T (p.Arg246X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, a commonly known mechanism for disease. The variant allele was found at a frequency of 0.00038 in 251426 control chromosomes in the gnomAD database, including 1 homozygote. As the exact prevalence of this disorder is not established, this frequency does not allow conclusions about variant significance. c.736C>T has been reported in the literature as a homozygous or compound heterozygous genotype in multiple individuals affected with Glycogen Storage Disorder Due To Hepatic Glycogen Synthase Deficiency (example, Orho_1998, Bachrach_2002, Soggia_2010, Cakar_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Orho_1998). The most pronounced variant effect results in complete abolishment of normal Glycogen synthase activity in-vitro. The following publications have been ascertained in the context of this evaluation (PMID: 12072888, 32374048, 33502066, 9691087, 20051115). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 14, 2018	The GYS2 c.736C>T (p.Arg246Ter) variant is a stop-gained variant that has been reported in five studies in which it is found in a total of six individuals from five unrelated families affected with the liver presentation of glycogen storage disease type 0 (GSD 0), including three individuals who carried the variant in a homozygous state (including one sibling pair), and in three individuals who carried the variant in a compound heterozygous state (Orho et al. 1998; Bachrach et al. 2002; Soggia et al. 2010; Brown et al. 2015; Kasapkara et al. 2017). The p.Arg246Ter variant was also detected in a heterozygous state in five family members of patients, one of whom was described as glucose intolerant. The variant was absent from 400 control chromosomes and is reported at a frequency of 0.002047 in the South Asian population of the Genome Aggregation Database. There is one homozygote present in the Genome Aggregation Database which can be explained by the variable presentation of liver GSD 0 which may go undetected even in adulthood. Based on the collective evidence, the c.736C>T (p.Arg246Ter) variant is classified as pathogenic for the liver form of glycogen storage disease type 0. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 26, 2023	This sequence change creates a premature translational stop signal (p.Arg246*) in the GYS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic (PMID: 9691087). This variant is present in population databases (rs121918419, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This premature translational stop signal has been observed in individuals with glycogen storage disease type 0 (PMID: 9691087, 20051115, 25070466). ClinVar contains an entry for this variant (Variation ID: 16049). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 03, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed stop gained variant c.736C>T(p.Arg246Ter) in GYS2 gene has been reported in homozygous state and compound heterozygous in multiple individuals with glycogen storage disease (Kasapkara ÇS, et al., 2017, Soggia AP, et al., 2010). Experimental studies demonstrate a damaging effect of this variant leading to severely impaired glycogen synthase activity (Orho M, et al., 1998). The variant has 0.03% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic/Pathogenic (Multiple submissions). Computational evidence (Mutation Taster - Disease causing) predicts damaging effect on protein structure and function for this variant. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYS2 are known to be pathogenic. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS).The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000016049, PMID:9691087). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000354, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with liver glycogen storage disease 0 (MIM#240600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable clinical phenotypes have been reported in affected individuals within the same family (PMIDs: 18341095, 28245189, 32395408). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (98 heterozygotes, 1 homozygote). (SP) 0701 - Other variants resulting in a premature termination codon comparable to the one identified in this case have very strong previous evidence for pathogenicity. At least 10 other NMD-predicted variants have been reported in affected individuals (PMID: 32779500) or as likely pathogenic/pathogenic in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with glycogen synthase deficiency (PMIDs: 12072888, 28245189, 32779500) and as likely pathogenic/pathogenic in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Glycogen storage disease

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 17, 2015

The p.Arg246X variant in GYS2 has been reported in 2 individuals with glycogen s torage disease type 0, one of whom was homozygous and one was compound heterozyg ous for this variant (Ohno 1998 and Soggia 2010). This variant has also been ide ntified in 0.2% (31/16479) of South Asian chromosomes by the Exome Aggregation C onsortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121918419). This nonsen se variant leads to a premature termination codon at position 246, which is pred icted to lead to a truncated or absent protein. Loss of function of the GYS2 gen e is associated with glycogen storage disease type 0. In summary, although addit ional studies are required to fully establish its clinical significance, the p.A rg246X variant is likely pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Apr 05, 2021

ACMG classification criteria: PVS1, PM3 -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2022

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: severely impaired glycogen synthase activity (Orho et al., 1998); This variant is associated with the following publications: (PMID: 25525159, 31589614, 32374048, 20051115, 29961766, 28245189, 30609409, 30487145, 31980526, 9691087) -

GYS2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 2023

The GYS2 c.736C>T variant is predicted to result in premature protein termination (p.Arg246*). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with glycogen storage disease (see for example, Figure 1, Orho et al. 1998. PubMed ID: 9691087; Bachrach et al. 2002. PubMed ID: 12072888; Figure 1, Soggia et al. 2010. PubMed ID: 20051115). This variant is reported in 0.21% of alleles in individuals of South Asian descent in gnomAD. Nonsense variants in GYS2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Uncertain

0.92

MutationTaster

Benign

1.0

Vest4

0.96

GERP RS

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over