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

Genomes: not found (cov: 21)

Consequence

GPC3
NM_004484.4 missense

Scores

3
6
8

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.68
Variant links:
Genes affected
GPC3 (HGNC:4451): (glypican 3) Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The protein encoded by this gene can bind to and inhibit the dipeptidyl peptidase activity of CD26, and it can induce apoptosis in certain cell types. Deletion mutations in this gene are associated with Simpson-Golabi-Behmel syndrome, also known as Simpson dysmorphia syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PS1
Transcript NM_004484.4 (GPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 11695
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.953
PP5
Variant X-133536201-C-G is Pathogenic according to our data. Variant chrX-133536201-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1500542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-133536201-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GPC3NM_004484.4 linkuse as main transcriptc.1666G>C p.Gly556Arg missense_variant 8/8 ENST00000370818.8
GPC3NM_001164617.2 linkuse as main transcriptc.1735G>C p.Gly579Arg missense_variant 9/9
GPC3NM_001164618.2 linkuse as main transcriptc.1618G>C p.Gly540Arg missense_variant 8/8
GPC3NM_001164619.2 linkuse as main transcriptc.1504G>C p.Gly502Arg missense_variant 7/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GPC3ENST00000370818.8 linkuse as main transcriptc.1666G>C p.Gly556Arg missense_variant 8/81 NM_004484.4 P1P51654-1

Frequencies

GnomAD3 genomes
Cov.:
21
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
21

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxOct 09, 2022Reported 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 19, 2021In 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.070
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;.;.
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.86
D;D;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Benign
-0.84
T
MutationAssessor
Benign
1.7
L;.;.
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.53
N;N;.
REVEL
Uncertain
0.35
Sift
Uncertain
0.0030
D;D;.
Sift4G
Uncertain
0.036
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.51
MutPred
0.82
Gain of methylation at G556 (P = 0.0475);.;.;
MVP
0.88
MPC
0.79
ClinPred
0.82
D
GERP RS
4.8
Varity_R
0.37
gMVP
0.72

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-132670229; API