rs370652040

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_004130.4(GYG1):c.143+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000341 in 1,613,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

GYG1
NM_004130.4 splice_region, intron

Scores

Splicing: ADA: 0.9460

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.94

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

polyglucosan body myopathy type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, PanelApp Australia, ClinGen
glycogen storage disease XV
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

GYG1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 3-148994280-G-C is Pathogenic according to our data. Variant chr3-148994280-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
GYG1	NM_004130.4 link	c.143+3G>C	splice_region_variant, intron_variant	Intron 2 of 7	ENST00000345003.9	NP_004121.2
GYG1	NM_001184720.2 link	c.143+3G>C	splice_region_variant, intron_variant	Intron 2 of 6		NP_001171649.1
GYG1	NM_001184721.2 link	c.143+3G>C	splice_region_variant, intron_variant	Intron 2 of 5		NP_001171650.1
GYG1	XM_017006275.2 link	c.-34-2022G>C	intron_variant	Intron 1 of 5		XP_016861764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYG1	ENST00000345003.9 link	c.143+3G>C		splice_region_variant, intron_variant	Intron 2 of 7	1	NM_004130.4	ENSP00000340736.4

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000199

AC:

AN:

251254

AF XY:

0.000243

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000405

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000357

AC:

522

AN:

1461696

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

251

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000455

AC:

506

AN:

1111858

Other (OTH)

AF:

0.000215

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000190

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41556

American (AMR)

AF:

0.000131

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68020

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000264

Hom.:

Bravo

AF:

0.000185

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Apr 17, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that c.143+3 G>C results in abnormal splicing, leading to skipping of exon 2 (PMID: 25272951); This variant is associated with the following publications: (PMID: 27663060, 25272951, 27066558, 26652229, 26203156, 28256728, 29264399, 34426522, 31589614, 32905144) -

Mar 15, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

GYG1: PP1:Strong, PM2, PM3, PS3:Moderate -

Polyglucosan body myopathy type 2

Pathogenic:2

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The heterozygous c.143+3G>C variant in GYG1 was identified by our study, in the compound heterozygous state with a pathogenic variant (ClinVar Variation ID: 162665), in one individual with polyglucosan body myopathy. This individual also carried a pathogenic variant (ClinVar Variation ID: 162665), however the phase of these variants are unknown at this time. The c.143+3G>C variant has been previously reported in 16 unrelated individuals with polyglucosan body myopathy 2 (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156) and segregated with disease in 3 affected relatives in one family (PMID: 29264399), but has been identified in 0.04% (50/128982) of European (non-Finnish) chromosomes by the by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs370652040). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. Of these 16 previously reported unrelated individuals, 11 were homozygotes (PMID: 25272951, PMID: 26652229, PMID: 29264399, PMID: 29205400, PMID: 27066558, PMID: 26203156), and one was a reported compound heterozygote who carried a pathogenic variant in unknown phase (PMID: 29264399), and the patient identified by our study was also a reported compound heterozygote who carried a pathogenic variant in unknown phase (ClinVar Variation ID: 162665), which increases the likelihood that the c.143+3G>C variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 162661) and has been interpreted as pathogenic by the NIH Undiagnosed Disease Network, Invitae, CeGaT Center for Human Genetics Tuebingen, GeneDx, OMIM, and PerkinElmer Genomics. RT-PCR analysis of RNA from patient skeletal muscle tissue shows skipping of exon 2 and frameshift beginning at position 3 and leading to a premature termination codon 4 amino acids downstream (PMID: 25272951). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive polyglucosan body myopathy 2. ACMG/AMP Criteria applied: PS3_Moderate, PM3_Strong, PP1 (Richards 2015). -

Dec 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Pathogenic:1

Dec 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 2 of the GYG1 gene. It does not directly change the encoded amino acid sequence of the GYG1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs370652040, gnomAD 0.04%). This variant has been observed in individuals with polyglucosan body myopathy (PMID: 25272951, 26652229, 29264399). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162661). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 2, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 25272951). For these reasons, this variant has been classified as Pathogenic. -

Glycogen storage disease XV

Pathogenic:1

Sep 17, 2019

Undiagnosed Diseases Network, NIH

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

(source)

DANN

Benign

0.90

PhyloP100

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: -20

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over