rs143137713

Positions:

chr3-148996462-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PP5_Very_StrongBS2

The NM_004130.4(GYG1):c.304G>C(p.Asp102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,688 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D102V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

GYG1
NM_004130.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15U:3

Conservation

PhyloP100: 9.57

Variant links:

Genes affected

GYG1 (HGNC:4699): (glycogenin 1) This gene encodes a member of the glycogenin family. Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction. This reaction is followed by elongation and branching of the polymer, catalyzed by glycogen synthase and branching enzyme, to form glycogen. This gene is expressed in muscle and other tissues. Mutations in this gene result in glycogen storage disease XV. This gene has pseudogenes on chromosomes 1, 8 and 13 respectively. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

GYG1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PP5

Variant 3-148996462-G-C is Pathogenic according to our data. Variant chr3-148996462-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 162663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-148996462-G-C is described in Lovd as [Likely_pathogenic].

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GYG1	NM_004130.4 linkuse as main transcript	c.304G>C	p.Asp102His	missense_variant	3/8	ENST00000345003.9
GYG1	NM_001184720.2 linkuse as main transcript	c.304G>C	p.Asp102His	missense_variant	3/7
GYG1	NM_001184721.2 linkuse as main transcript	c.304G>C	p.Asp102His	missense_variant	3/6
GYG1	XM_017006275.2 linkuse as main transcript	c.127G>C	p.Asp43His	missense_variant	2/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYG1	ENST00000345003.9 linkuse as main transcript	c.304G>C	p.Asp102His	missense_variant	3/8	1	NM_004130.4		P46976-1

Frequencies

GnomAD3 genomes

AF:

0.00106

AC:

161

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00102

AC:

257

AN:

251340

Hom.:

AF XY:

0.00101

AC XY:

137

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00191

AC:

2787

AN:

1461388

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

1368

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000938

Gnomad4 NFE exome

AF:

0.00237

Gnomad4 OTH exome

AF:

0.00131

GnomAD4 genome

AF:

0.00106

AC:

161

AN:

152300

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00154

Hom.:

Bravo

AF:

0.00118

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000914

AC:

111

EpiCase

AF:

0.00207

EpiControl

AF:

0.00202

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GYG1: PM3:Strong, PM2:Supporting, PP3 -
Uncertain significance, flagged submission	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, flagged submission	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2023	PP3, PP4, PM3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 27, 2023	Published functional studies demonstrate a damaging effect; the mutated glycogenin-1 protein lost its ability to autoglucosylate, and was therefore unable to form the primer for normal glycogen synthesis (Malfatti et al., 2014; Hedberg-Oldfors et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29422440, 31791869, 34662886, 25272951, 27718144, 25741868, 32477874, 31980526, 34426522, 31589614, 32528171) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2022	- -

Polyglucosan body myopathy type 2

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 07, 2023	Variant summary: GYG1 c.304G>C (p.Asp102His) 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 0.001 in 251340 control chromosomes. This frequency does not allow conclusions about variant significance. c.304G>C has been reported in the literature as a biallelic homozygous or compound heterozygous genotype in multiple individuals affected with features of Polyglucosan Body Myopathy Type 2 (example, PMID: 25272951, 27718144, 32528171). These data indicate that the variant is likely to be associated with disease. To our knowledge, no quantifiable variant specific experimental evidence demonstrating an impact on protein function has been reported. Although one study reported that an assay of autoglucosylation in vitro did not show any gel shift after the addition of UDP glucose, suggesting nonfunctional glycogenin-1 (PMID: 25272951). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (P/LP, n=6; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PM3,PS1,PP3,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 25, 2022	- -

Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 102 of the GYG1 protein (p.Asp102His). This variant is present in population databases (rs143137713, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with glycogenin 1 deficiency (PMID: 25272951, 27718144). ClinVar contains an entry for this variant (Variation ID: 162663). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GYG1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GYG1 function (PMID: 25272951, 27718144). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Glycogen storage disease XV

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	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 reported mechanism of disease in this gene and is associated with polyglucosan body myopathy 2 (MIM#616199) and glycogen storage disease XV (MIM#613507). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. With multiple cases reporting abnormal glycogen storage, and varying muscular phenotypes, age of onset, and sometimes severe cardiac disorders (PMID: 31791869, PMID: 32477874). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (290 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl transferase family 8 domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been identified in at least six unrelated affected individuals (ClinVar, PMID:25272951, PMID:27718144, PMID: 31791869, PMID: 32477874). It has also been reported as a VUS in ClinVar, including one as a VUS favouring pathogenic and two without further information provided. (SP) 0906 - Segregation evidence for this variant is inconclusive. A homozygous sibling of an affected individual showed no clinical symptoms at 53 years of age (PMID:27718144). (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional studies from a homozygous individual demonstrated protein activity was abolished in cardiac muscle. (PMID:27718144). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2022	- -

Glycogen storage disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Nov 05, 2023

This sequence change in GYG1 is predicted to replace aspartic acid with histidine at codon 102, p.(Asp102His). The aspartic acid residue is highly conserved (100 vertebrates, UCSC), and is located in located in the highly conserved DxD motif, which is defined as a critical functional domain (PMID: 27718144). There is a moderate physicochemical difference between aspartic acid and histidine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.18% (235/129,154 alleles) in the European (non-Finnish) population. This variant has been detected in at least six individuals with muscle glycogenin 1 deficiency. Of those individuals, three individuals were homozygous presenting with cardiomyopathy and three were compound heterozygous with a second pathogenic variant presenting with neuromuscular features (PMID: 25272951, 27718144, 31791869, 32477874). At least one patient with this variant displayed defective glycogenin-1 function in muscle biopsies after alpha-amylase treatment, which is highly specific for muscle glycogenin 1 deficiency (PMID: 27718144, 31791869). An in vitro functional assay with limited validation demonstrated the variant altered the autoglycosylation function of the protein (PMID: 27718144). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.942). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_Strong, PM1, PP3_Moderate, PP4, PS3_Supporting. -

GYG1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2023

The GYG1 c.304G>C variant is predicted to result in the amino acid substitution p.Asp102His. This variant has been previously reported in the compound heterozygous state with a protein truncating variant in two different patients with polyglucosan body myopathy (Malfatti et al. 2014. PubMed ID: 25272951; Lefeuvre et al. 2020. PubMed ID: 32477874). The same variant was also found in the homozygous state via exome sequencing in three unrelated individuals who presented with cardiomyopathy (Hedberg-Oldfors et al. 2017. PubMed ID: 27718144). In all of these studies, morphological analysis revealed accumulation of glycogen and/or polyglucosan bodies in either skeletal or cardiac muscle. Furthermore, in vitro studies showed that the p.Asp102His change lead to the loss of GYG1 autoglucosylation, which would result in a non-functional GYG1 protein (Malfatti et al. 2014. PubMed ID: 25272951; Hedberg-Oldfors et al. 2017. PubMed ID: 27718144). This variant is reported in 0.18% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-148714249-G-C). This variant is interpreted as pathogenic. -

not specified

Uncertain:1

Uncertain significance, flagged submission

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 30, 2019

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp102His variant in GYG1 has been reported in the compound heterozygous state in 1 individual with polyglucosan body myopathy and in the homozygous state in 3 individuals with cardiomyopathy and no muscle weakness but with abnormal glycogen storage as indicated by an endomyocardial biopsy (Malfatti 2014, Hedberg-Oldfors 2017). An in vitro functional study suggests that the p.Asp102His could cause defects in auto-glycosylation upon addition of UPD glucose, however, these types of assays may not accurately represent biological function (Malfatti 2014). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 162663) and has been identified in 0.18% (235/129154) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PM3, PP3, PS3_Supporting, BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.87

D;.;.;.;.;.;D;.

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Uncertain

0.61

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.3

H;.;H;.;H;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.8

D;.;D;D;D;D;D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D

Polyphen

1.0

D;D;D;D;.;.;.;.

Vest4

0.99

MVP

1.0

MPC

0.56

ClinPred

0.89

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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