19-3115014-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5

The NM_002067.5(GNA11):c.547C>T(p.Arg183Cys) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R183R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

GNA11
NM_002067.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:1

Conservation

PhyloP100: 2.50

Variant links:

Genes affected

GNA11 (HGNC:4379): (G protein subunit alpha 11) The protein encoded by this gene belongs to the family of guanine nucleotide-binding proteins (G proteins), which function as modulators or transducers in various transmembrane signaling systems. G proteins are composed of 3 units: alpha, beta and gamma. This gene encodes one of the alpha subunits (subunit alpha-11). Mutations in this gene have been associated with hypocalciuric hypercalcemia type II (HHC2) and hypocalcemia dominant 2 (HYPOC2). Patients with HHC2 and HYPOC2 exhibit decreased or increased sensitivity, respectively, to changes in extracellular calcium concentrations. [provided by RefSeq, Dec 2013]

GNA11 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GNA11 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 13 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.768 (above the threshold of 3.09). Trascript score misZ: 3.8723 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant hypocalcemia, familial hypocalciuric hypercalcemia 2, autosomal dominant hypocalcemia 2.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 19-3115014-C-T is Pathogenic according to our data. Variant chr19-3115014-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 548668.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=5, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GNA11	NM_002067.5 link	c.547C>T	p.Arg183Cys	missense_variant	Exon 4 of 7	ENST00000078429.9	NP_002058.2	P29992

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GNA11	ENST00000078429.9 link	c.547C>T	p.Arg183Cys	missense_variant	Exon 4 of 7	1	NM_002067.5	ENSP00000078429.3	P29992
GNA11	ENST00000587636.1 link	c.91C>T	p.Arg31Cys	missense_variant	Exon 2 of 6	5		ENSP00000465935.1	K7EL62
GNA11	ENST00000588401.1 link	c.67C>T	p.Arg23Cys	missense_variant	Exon 1 of 2	2		ENSP00000479797.1	A0A087WVZ3
GNA11	ENST00000586763.1 link	n.*11C>T		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Capillary malformation

Pathogenic:2

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A GNA11 c.547C>T p.(Arg183Cys) variant was identified at an allelic fraction consistent with somatic origin. The variant has been reported in multiple individuals affected with capillary malformations (Thomas AC et al. PMID: 26778290; Siegel DH et al. PMID: 29174369; Polubothu S et al. PMID: 31838126). The GNA11 c.547C>T p.(Arg183Cys) variant has been reported in numerous cases in the cancer database COSMIC (COSMIC Genomic Mutation ID COSV50017316 ) and it has been reported in the ClinVar database as a pathogenic/likely pathogenic somatic variant by multiple submitters (ClinVar Variation ID:548668). The variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. This variant resides within the GTP-binding site (amino acids Leu180‚ÄìArg183) of GNA11, which is critical for its function and constitutes a mutational hotspot (Conklin BR et al., PMID: 1309740; Van Raamsdonk CD et al., PMID: 21083380; O'Hayre M et al., PMID: 23640210). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on GNA11 function. In support of this prediction, functional studies demonstrate that this variant leads to increased mitogen-activated protein kinase (MAPK) signaling and cellular proliferation in multiple cell lines (Thomas AC et al., PMID: 26778290; Ma J et al., PMID: 33262460). Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the GNA11 c.547C>T p.(Arg183Cys) variant is classified as pathogenic. -

not provided

Pathogenic:1Uncertain:1

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 183 of the GNA11 protein (p.Arg183Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GNA11-associated somatic overgrowth syndromes but it has not been associated with autosomal dominant hypocalcemia or hypercalcemia. (PMID: 31726051, 35351629, 35777808). ClinVar contains an entry for this variant (Variation ID: 548668). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GNA11 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNA11 function (PMID: 26778290, 35777808). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

May 06, 2021

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This same somatic GNA11 missense mutation has been reported in other affected individuals with capillary malformations causing overgrowth (PMID: 28120216), vascular tumors (PMID: 27476652) and phacomatosis pigmentovascularis (PMID: 31872050). -

Lobular capillary hemangiomas

Pathogenic:1

Jul 28, 2016

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Segmental undergrowth associated with capillary malformation

Pathogenic:1

Apr 06, 2021

Institute of Medical and Molecular Genetics, Hospital Universitario La Paz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CLOVES syndrome

Pathogenic:1

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.1

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.82

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MutPred

0.93

Loss of methylation at R183 (P = 0.0577);

MVP

0.97

MPC

3.0

ClinPred

1.0

GERP RS

2.8

Varity_R

0.95

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over