1-17044849-G-A
Variant summary
Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM1PP3
The NM_003000.3(SDHB):c.112C>T(p.Arg38Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R38H) has been classified as Likely benign.
Frequency
Consequence
NM_003000.3 missense
Scores
Clinical Significance
Conservation
Publications
- Carney-Stratakis syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
- gastrointestinal stromal tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- pheochromocytomaInheritance: AD Classification: DEFINITIVE Submitted by: G2P
- pheochromocytoma/paraganglioma syndrome 4Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
- mitochondrial diseaseInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
- renal cell carcinomaInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- mitochondrial complex 2 deficiency, nuclear type 4Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Cowden diseaseInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- mitochondrial complex II deficiencyInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Uncertain_significance. The variant received 3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152108Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.0000199 AC: 5AN: 251262 AF XY: 0.0000147 show subpopulations
GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461678Hom.: 0 Cov.: 32 AF XY: 0.0000426 AC XY: 31AN XY: 727152 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000592 AC: 9AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74300 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Gastrointestinal stromal tumor Uncertain:3
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not provided Uncertain:2
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with pheochromocytoma or paraganglioma (de Cubas et al., 2013; Parisien-La Salle et al., 2022); This variant is associated with the following publications: (PMID: 34072806, 23660872, 26269449, 29641532, 34750850) -
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Pheochromocytoma/paraganglioma syndrome 4 Uncertain:2
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
not specified Uncertain:1
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Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
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Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the SDHB protein (p.Arg38Cys). This variant is present in population databases (rs202119350, gnomAD 0.006%). This missense change has been observed in individuals with paraganglioma (PMID: 23660872; internal data). ClinVar contains an entry for this variant (Variation ID: 371801). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHB protein function. Experimental studies have shown that this missense change affects SDHB function (PMID: 37840772). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R38C variant (also known as c.112C>T), located in coding exon 2 of the SDHB gene, results from a C to T substitution at nucleotide position 112. The arginine at codon 38 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been previously identified in an individual with metastatic parganglioma (de Cubas AA et al. Endocr. Relat. Cancer. 2013 Aug;20(4):477-93), but was also identified in 2/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One 2018 Apr;13(4):e0194098). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at