chr17-42911000-G-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000151.4(G6PC1):c.648G>T(p.Leu216=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,614,166 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L216L) has been classified as Likely benign.
Frequency
Consequence
NM_000151.4 synonymous
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
G6PC1 | NM_000151.4 | c.648G>T | p.Leu216= | synonymous_variant | 5/5 | ENST00000253801.7 | |
G6PC1 | NM_001270397.2 | c.*40G>T | 3_prime_UTR_variant | 5/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
G6PC1 | ENST00000253801.7 | c.648G>T | p.Leu216= | synonymous_variant | 5/5 | 1 | NM_000151.4 | P1 | |
G6PC1 | ENST00000585489.1 | c.*40G>T | 3_prime_UTR_variant | 4/4 | 5 | ||||
G6PC1 | ENST00000592383.5 | c.*40G>T | 3_prime_UTR_variant | 5/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251236Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135758
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29AN XY: 727244
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74456
ClinVar
Submissions by phenotype
Glycogen storage disease due to glucose-6-phosphatase deficiency type IA Pathogenic:11Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change affects codon 216 of the G6PC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the G6PC protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs80356484, gnomAD 0.1%). This variant has been observed in individual(s) with glycogen storage disease type 1 (PMID: 7668282, 10797430, 23000067, 23486339, 24980439; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as g727t. ClinVar contains an entry for this variant (Variation ID: 12003). Studies have shown that this variant results in partial deletion of exon 5 and introduces a new termination codon (PMID: 7668282, 10748407). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 23, 2016 | Variant summary: The G6PC c.648G>T (p.Leu216Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant may strengthen a cryptic 3' splicing acceptor site in exon 5. ESE finder predicts that this variant may create a novel SRp40 binding site. These predictions have been confirmed by at least one functional study (Kajihara_1995), showing this variant leads to a deletion of the front 91 nt of exon 5 in the patient's cDNA and this deletion results in a premature stop codon. This variant was found in 11/121428 control chromosomes at a frequency of 0.0000906, which does not exceed the estimated maximal expected allele frequency of a pathogenic G6PC variant (0.0017321). This variant has been reported as the most common pathogenic variant in GSD1a patients in East Asia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 13, 2000 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 28, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 11, 2019 | The G6PC c.648G>T (p.Leu216Leu) synonymous variant is an established pathogenic variant that occurs in approximately 91% of Japanese glucogen storage disease type 1 (GSD1) alleles, 75% of Korean GSD1 alleles, and 54% of Chinese GSD1 alleles (Chou et al. 2008; Froissart et al. 2011; Bali 2013). Across a selection of available literature, the p.Leu216Leu variant has been reported in at least 55 individuals with glycogen storage disease type 1, including 47 in a homozygous state and eight in a compound heterozygous state (Kajihara et al. 1995; Akanuma et al. 2000). The p.Leu216Leu variant is reported at a frequency of 0.001271 in the East Asian population in the Exome Aggregation Consortium. The variant, although far from a splice junction, produces an aberrant transcript that eliminates 91 nucleotides and alters the reading frame, creating a premature termination at Tyr202 (Kajihara et al. 1995; Akanuma et al. 2000; Bali et al. 2013). Based on the collective evidence, the p.Leu216 variant is classified as pathogenic for glycogen storage disease type 1. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely pathogenic, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 18, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Mar 22, 2022 | Synonymous variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 7668282, PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012003, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000873). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual(PMID: 23000067, 11851840). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 20, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 11, 2024 | Reported as a common pathogenic variant in association with GSD1a among individuals of Japanese, Korean, and Chinese backgrounds (PMID: 18449899); Published functional studies demonstrate this variant results in a deletion of 91 base pairs from exon 5 (PMID: 7668282, 10748407); Also known as G727T using alternate nomenclature; This variant is associated with the following publications: (PMID: 10797430, 24980439, 31109299, 32046761, 32924126, 10748407, 33763395, 36160031, 36452356, 36595986, 36167523, 35314707, 35257483, 35783312, 18449899, 37788110, 7668282) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at