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

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

10
7
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:11

Conservation

PhyloP100: 1.18

Publications

4 publications found
Variant links:
Genes affected
SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]
SDHB Gene-Disease associations (from GenCC):
  • Carney-Stratakis syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
  • gastrointestinal stromal tumor
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
  • hereditary pheochromocytoma-paraganglioma
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
  • pheochromocytoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • pheochromocytoma/paraganglioma syndrome 4
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
  • mitochondrial disease
    Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
  • renal cell carcinoma
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • mitochondrial complex 2 deficiency, nuclear type 4
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Cowden disease
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • mitochondrial complex II deficiency
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 uncertain in NM_003000.3
PP3
MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHBNM_003000.3 linkc.112C>T p.Arg38Cys missense_variant Exon 2 of 8 ENST00000375499.8 NP_002991.2 P21912
SDHBNM_001407361.1 linkc.112C>T p.Arg38Cys missense_variant Exon 2 of 8 NP_001394290.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHBENST00000375499.8 linkc.112C>T p.Arg38Cys missense_variant Exon 2 of 8 1 NM_003000.3 ENSP00000364649.3 P21912

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152108
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000103
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000199
AC:
5
AN:
251262
AF XY:
0.0000147
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000404
AC:
59
AN:
1461678
Hom.:
0
Cov.:
32
AF XY:
0.0000426
AC XY:
31
AN XY:
727152
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.0000224
AC:
1
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.0000765
AC:
2
AN:
26134
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53332
Middle Eastern (MID)
AF:
0.000173
AC:
1
AN:
5766
European-Non Finnish (NFE)
AF:
0.0000450
AC:
50
AN:
1111904
Other (OTH)
AF:
0.0000662
AC:
4
AN:
60384
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.488
Heterozygous variant carriers
0
3
6
10
13
16
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152108
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74300
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41416
American (AMR)
AF:
0.0000655
AC:
1
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10590
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000103
AC:
7
AN:
68028
Other (OTH)
AF:
0.00
AC:
0
AN:
2086
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.558
Heterozygous variant carriers
0
1
2
3
4
5
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000359
Hom.:
0
Bravo
AF:
0.0000453
ExAC
AF:
0.0000330
AC:
4
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gastrointestinal stromal tumor Uncertain:3
Apr 02, 2021
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 28, 2019
Mendelics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Mar 10, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:2
Jul 21, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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) -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:research

- -

Pheochromocytoma/paraganglioma syndrome 4 Uncertain:2
Apr 24, 2023
Myriad Genetics, Inc.
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Dec 08, 2015
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

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
Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
Jan 07, 2025
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 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
May 07, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.72
D;.
Eigen
Uncertain
0.19
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.80
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
3.4
M;.
PhyloP100
1.2
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-4.2
D;.
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
D;.
Sift4G
Uncertain
0.013
D;D
Polyphen
1.0
D;.
Vest4
0.71
MutPred
0.49
Loss of MoRF binding (P = 7e-04);.;
MVP
0.96
MPC
0.55
ClinPred
0.91
D
GERP RS
4.7
PromoterAI
-0.020
Neutral
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.49
gMVP
0.75
Mutation Taster
=15/85
disease causing

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

Other links and lift over

dbSNP: rs202119350; hg19: chr1-17371344; API