X-133536201-C-T

Variant names:

• chrX-133536201-C-T
• rs267606850
• NM_004484.4:c.1666G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS1_Very_Strong PM2 PP3_Strong PP5_Very_Strong

The NM_004484.4(GPC3):​c.1666G>A​(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 the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GPC3 NM_004484.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.68
• Publications: 5 publications found

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]

GPC3 Gene-Disease associations (from GenCC):

• Simpson-Golabi-Behmel syndrome

  Inheritance: XL Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Simpson-Golabi-Behmel syndrome type 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PS1: Transcript NM_004484.4 (GPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1500542
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant X-133536201-C-T is Pathogenic according to our data. Variant chrX-133536201-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPC3	NM_004484.4	c.1666G>A	p.Gly556Arg	missense_variant	Exon 8 of 8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1735G>A	p.Gly579Arg	missense_variant	Exon 9 of 9		NP_001158089.1
GPC3	NM_001164618.2	c.1618G>A	p.Gly540Arg	missense_variant	Exon 8 of 8		NP_001158090.1
GPC3	NM_001164619.2	c.1504G>A	p.Gly502Arg	missense_variant	Exon 7 of 7		NP_001158091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPC3	ENST00000370818.8	c.1666G>A	p.Gly556Arg	missense_variant	Exon 8 of 8	1	NM_004484.4	ENSP00000359854.3

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1 Pathogenic:1

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

May 26, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G556R variant (also known as c.1666G>A), located in coding exon 8 of the GPC3 gene, results from a G to A substitution at nucleotide position 1666. The glycine at codon 556 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in an individual diagnosed with Simpson-Golabi-Behmel syndrome (SGBS) who presented with ischemic stroke due to a dissection of the right internal cartoid artery (Pénisson-Besnier I et al. Am. J. Med. Genet. A, 2008 Feb;146A:464-7). In one functional study, authors showed that this alteration may reduce the ability of GPC3 protein to inhibit Hedgehog signaling during development (Shi W et al. Am. J. Med. Genet. A, 2009 Mar;149A:552-4). In addition, this alteration was detected in two unrelated individuals from a cohort of patients with SGBS phenotypes; however, specific clinical information on these two individuals was not provided (Cottereau E et al. Am J Med Genet C Semin Med Genet, 2013 May;163C:92-105). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Aug 08, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that this variant impairs the function of the GPC3 protein (PMID: 19215053); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31826854, 18203194, 29637653, 34547244, 23606591, 19215053) -

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	0.58	D
LIST_S2	Benign	0.86	D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		2.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.53	N;N;.
REVEL	Uncertain	0.33
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		0.88	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.72
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606850; hg19: chrX-132670229;