19-3115014-C-T

Variant names:

• chr19-3115014-C-T
• rs1555702147
• NM_002067.5:c.547C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS1 PM2 PM5 PP2 PP3_Strong PP5

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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R183H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GNA11 NM_002067.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 2.50
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant hypocalcemia 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• congenital hemangioma

  Inheritance: AD Classification: STRONG Submitted by: G2P
• familial hypocalciuric hypercalcemia 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet
• autosomal dominant hypocalcemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS1: Transcript NM_002067.5 (GNA11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-3115015-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 4279982.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 congenital hemangioma, familial hypocalciuric hypercalcemia 2, autosomal dominant hypocalcemia 2, autosomal dominant hypocalcemia.
• 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 VariationId is 548668.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002067.5. 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
	GNA11	NM_002067.5	MANE Select	c.547C>T	p.Arg183Cys	missense	Exon 4 of 7	NP_002058.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GNA11	ENST00000078429.9	TSL:1 MANE Select	c.547C>T	p.Arg183Cys	missense	Exon 4 of 7	ENSP00000078429.3
	GNA11	ENST00000587636.1	TSL:5	c.91C>T	p.Arg31Cys	missense	Exon 2 of 6	ENSP00000465935.1
	GNA11	ENST00000588401.1	TSL:2	c.67C>T	p.Arg23Cys	missense	Exon 1 of 2	ENSP00000479797.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:8 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:1

Dec 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously reported as a pathogenic or benign germline variant to our knowledge; However, it has been reported as a somatic variant in multiple individuals with uveal melanoma, lobular capillary hemangiomas, diffuse capillary malformations, phakomatosis pigmentovascularis with dermal melanocytosis, or Cutis marmorata telangiectatica congenita (PMID: 21083380, 27476652, 28120216, 26778290, 35351629); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrated increased phosphorylation resulting in activation of the p38 MAPK pathway (PMID: 26778290, 27476652); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27476652, 28194446, 28120216, 21083380, 26778290, 35351629)

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).

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GNA11: PM2, PM5, PS3:Moderate, PS4:Moderate, PP2, PP3

Capillary malformation Pathogenic:2

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.

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

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
PhyloP100		2.5
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
PromoterAI		0.044	Neutral
Varity_R		0.95
gMVP		0.99
Mutation Taster		=65/35	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: rs1555702147; hg19: chr19-3115012; COSMIC: COSV50017316; COSMIC: COSV50017316;