X-133753919-G-A

Variant names:

• chrX-133753919-G-A
• rs104894855
• NM_004484.4:c.595C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004484.4(GPC3):​c.595C>T​(p.Arg199*) variant causes a stop gained change. 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GPC3 NM_004484.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.13
• Publications: 4 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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-133753919-G-A is Pathogenic according to our data. Variant chrX-133753919-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	NM_004484.4	MANE Select	c.595C>T	p.Arg199*	stop_gained	Exon 3 of 8	NP_004475.1
	GPC3	NM_001164617.2		c.595C>T	p.Arg199*	stop_gained	Exon 3 of 9	NP_001158089.1
	GPC3	NM_001164618.2		c.547C>T	p.Arg183*	stop_gained	Exon 3 of 8	NP_001158090.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPC3	ENST00000370818.8	TSL:1 MANE Select	c.595C>T	p.Arg199*	stop_gained	Exon 3 of 8	ENSP00000359854.3
	GPC3	ENST00000394299.7	TSL:1	c.595C>T	p.Arg199*	stop_gained	Exon 3 of 9	ENSP00000377836.2
	GPC3	ENST00000631057.2	TSL:1	c.433C>T	p.Arg145*	stop_gained	Exon 2 of 7	ENSP00000486325.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Simpson-Golabi-Behmel syndrome type 1 Pathogenic:1

May 22, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Nov 04, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 29637653, 26633542, 10814714)

Wilms tumor 1 Pathogenic:1

Mar 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 11689). This premature translational stop signal has been observed in individual(s) with Simpson-Golabi-Behmel syndrome (PMID: 10814714). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg199*) in the GPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GPC3 are known to be pathogenic (PMID: 10402475, 12713262, 17603795).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		6.1
Vest4		0.99
GERP RS		5.5
PromoterAI		-0.0053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/198	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: rs104894855; hg19: chrX-132887946; COSMIC: COSV63668697; COSMIC: COSV63668697;