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
Consequence
NM_002067.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GNA11 | ENST00000078429.9 | c.547C>T | p.Arg183Cys | missense_variant | Exon 4 of 7 | 1 | NM_002067.5 | ENSP00000078429.3 | ||
GNA11 | ENST00000587636.1 | c.91C>T | p.Arg31Cys | missense_variant | Exon 2 of 6 | 5 | ENSP00000465935.1 | |||
GNA11 | ENST00000588401.1 | c.67C>T | p.Arg23Cys | missense_variant | Exon 1 of 2 | 2 | ENSP00000479797.1 | |||
GNA11 | ENST00000586763.1 | n.*11C>T | downstream_gene_variant | 3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Capillary malformation Pathogenic:2
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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
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. -
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
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Segmental undergrowth associated with capillary malformation Pathogenic:1
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CLOVES syndrome Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at