X-133536201-C-G

Position:

• chrX-133536201-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_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 (★★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.68

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• 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	Protein	UniProt
GPC3	NM_004484.4	c.1666G>C	p.Gly556Arg	missense_variant	8/8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1735G>C	p.Gly579Arg	missense_variant	9/9		NP_001158089.1
GPC3	NM_001164618.2	c.1618G>C	p.Gly540Arg	missense_variant	8/8		NP_001158090.1
GPC3	NM_001164619.2	c.1504G>C	p.Gly502Arg	missense_variant	7/7		NP_001158091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1666G>C	p.Gly556Arg	missense_variant	8/8	1	NM_004484.4	ENSP00000359854	P1

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

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: 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;