rs143137713

chr3-148996462-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP5

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 Conflicting classifications of pathogenicity (no stars). 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:3
• Conservation: PhyloP100: 9.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 3-148996462-G-C is Pathogenic according to our data. Variant chr3-148996462-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162663.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=7, Likely_pathogenic=6, Uncertain_significance=1}. Variant chr3-148996462-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152182 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00101 AC XY: 137 AN XY: 135872

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.: 2 Cov.: 31 AF XY: 0.00188 AC XY: 1368 AN XY: 727058

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.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74478

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.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000914 AC: 111

EpiCase AF: 0.00207

EpiControl AF: 0.00202

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:14 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:4 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 23, 2022	- -
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	Mayo Clinic Laboratories, Mayo Clinic	Apr 21, 2023	PP3, PP4, PM3, PS4_moderate -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	GYG1: PM3:Strong, PM2:Supporting, PP3 -

Polyglucosan body myopathy type 2 Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jan 25, 2022	- -
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. -
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, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 23, 2022	- -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	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 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 condition 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. -

Glycogen storage disease XV Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;.;.;.;.;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;H;.;H;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
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	D
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

Other links and lift over

dbSNP: rs143137713; hg19: chr3-148714249; COSMIC: COSV56049205; COSMIC: COSV56049205;