chrX-133536201-C-T

Position:

• chrX-133536201-C-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000370818.8(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 same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G556V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 21)
• Consequence: GPC3 ENST00000370818.8 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter 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 20 ACMG points.

• PS1: Transcript ENST00000370818.8 (GPC3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 1500542
• PM1: In a propeptide Removed in mature form (size 25) in uniprot entity GPC3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000370818.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-133536200-C-A is described in Lovd as [Likely_pathogenic].
• 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_single_submitter, 1 stars. Variant chrX-133536201-C-T 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>A	p.Gly556Arg	missense_variant	8/8	ENST00000370818.8	NP_004475.1
GPC3	NM_001164617.2	c.1735G>A	p.Gly579Arg	missense_variant	9/9		NP_001158089.1
GPC3	NM_001164618.2	c.1618G>A	p.Gly540Arg	missense_variant	8/8		NP_001158090.1
GPC3	NM_001164619.2	c.1504G>A	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>A	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, single submitter

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2009

- -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2017

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. -

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;.;.
MutationTaster	Benign	1.0	N;N;N
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

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

LitVar

Other links and lift over

dbSNP: rs267606850; hg19: chrX-132670229;