3-148994159-C-CT

Variant names:

• chr3-148994159-C-CT
• rs985019447
• NM_004130.4:c.26dupT

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004130.4(GYG1):​c.26dupT​(p.Thr10AsnfsTer47) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GYG1 NM_004130.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.974 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-148994159-C-CT is Pathogenic according to our data. Variant chr3-148994159-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 2926005.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYG1	NM_004130.4	c.26dupT	p.Thr10AsnfsTer47	frameshift_variant	Exon 2 of 8	ENST00000345003.9	NP_004121.2
GYG1	NM_001184720.2	c.26dupT	p.Thr10AsnfsTer47	frameshift_variant	Exon 2 of 7		NP_001171649.1
GYG1	NM_001184721.2	c.26dupT	p.Thr10AsnfsTer47	frameshift_variant	Exon 2 of 6		NP_001171650.1
GYG1	XM_017006275.2	c.-34-2142dupT		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	c.26dupT	p.Thr10AsnfsTer47	frameshift_variant	Exon 2 of 8	1	NM_004130.4	ENSP00000340736.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461158 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726920

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 Pathogenic:1

Oct 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr10Asnfs*47) in the GYG1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GYG1 are known to be pathogenic (PMID: 20357282, 25272951). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GYG1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs985019447; hg19: chr3-148711946;