19-3115014-C-T

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

16
2
1

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]

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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
GNA11NM_002067.5 linkc.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 Appris UniProt
GNA11ENST00000078429.9 linkc.547C>T p.Arg183Cys missense_variant Exon 4 of 7 1 NM_002067.5 ENSP00000078429.3 P29992
GNA11ENST00000587636.1 linkc.91C>T p.Arg31Cys missense_variant Exon 2 of 6 5 ENSP00000465935.1 K7EL62
GNA11ENST00000588401.1 linkc.67C>T p.Arg23Cys missense_variant Exon 1 of 2 2 ENSP00000479797.1 A0A087WVZ3
GNA11ENST00000586763.1 linkn.*11C>T downstream_gene_variant 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

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–Arg183) 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
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
32
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.97
D
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.80
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.1
H
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-7.7
D
REVEL
Pathogenic
0.82
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.86
MutPred
0.93
Loss of methylation at R183 (P = 0.0577);
MVP
0.97
MPC
3.0
ClinPred
1.0
D
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.

Other links and lift over

dbSNP: rs1555702147; hg19: chr19-3115012; COSMIC: COSV50017316; COSMIC: COSV50017316; API