rs267606850
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1PM2PP3_StrongPP5_Very_Strong
The NM_004484.4(GPC3):c.1666G>C(p.Gly556Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.
Frequency
Consequence
NM_004484.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GPC3 | NM_004484.4 | c.1666G>C | p.Gly556Arg | missense_variant | 8/8 | ENST00000370818.8 | |
GPC3 | NM_001164617.2 | c.1735G>C | p.Gly579Arg | missense_variant | 9/9 | ||
GPC3 | NM_001164618.2 | c.1618G>C | p.Gly540Arg | missense_variant | 8/8 | ||
GPC3 | NM_001164619.2 | c.1504G>C | p.Gly502Arg | missense_variant | 7/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GPC3 | ENST00000370818.8 | c.1666G>C | p.Gly556Arg | missense_variant | 8/8 | 1 | NM_004484.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 21
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 21
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2022 | Reported in the hemizygous state in a fetus with fetal akinesia in the published literature (Falb et al., 2021); Same amino acid substitution caused by a different nucleotide change (c.1666 G>A) has been reported in the published literature in association with Simpson-Golabi-Behmel syndrome (Vuillaume et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29637653, 19215053, 18203194, 34740919) - |
Wilms tumor 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 19, 2021 | 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. Experimental studies have shown that this missense change affects GPC3 function (PMID: 19215053). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This missense change has been observed in individuals with Simpson-Golabi-Behmel syndrome (PMID: 29637653). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 556 of the GPC3 protein (p.Gly556Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.