NM_003000.3:c.716C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PP3_Moderate

The NM_003000.3(SDHB):​c.716C>T​(p.Ser239Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,982 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. S239Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 9.30

Publications

3 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 4 ACMG points.

PM1
In a hotspot region, there are 7 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, 0.923

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SDHBNM_003000.3 linkc.716C>T p.Ser239Phe missense_variant Exon 7 of 8 ENST00000375499.8 NP_002991.2 P21912
SDHBNM_001407361.1 linkc.662C>T p.Ser221Phe missense_variant Exon 7 of 8 NP_001394290.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SDHBENST00000375499.8 linkc.716C>T p.Ser239Phe missense_variant Exon 7 of 8 1 NM_003000.3 ENSP00000364649.3 P21912

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000239
AC:
6
AN:
251464
AF XY:
0.0000294
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000192
AC:
28
AN:
1461804
Hom.:
0
Cov.:
31
AF XY:
0.0000261
AC XY:
19
AN XY:
727218
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44720
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39694
South Asian (SAS)
AF:
0.000197
AC:
17
AN:
86254
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53408
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000899
AC:
10
AN:
1111962
Other (OTH)
AF:
0.00
AC:
0
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.489
Heterozygous variant carriers
0
3
5
8
10
13
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:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74350
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41440
American (AMR)
AF:
0.00
AC:
0
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4826
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
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:
0.00
Hom.:
0
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Uncertain:2
Sep 11, 2024
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with phenylalanine at codon 239 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant, however the residue may be structurally important (PMID: 22904323). This variant has been reported in an individual affected with paraganglioma in the literature (PMID: 18382370). This variant has been identified in 6/251464 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Uncertain:1
Jul 11, 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; Identified in an individual with paraganglioma (Klein et al., 2008); This variant is associated with the following publications: (PMID: 22270996, 18382370, 26273102) -

Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
Nov 08, 2022
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The SDHB c.716C>T (p.Ser239Phe) missense change has a maximum frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/ ). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with metastatic paraganglioma (PMID: 18382370). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1
Aug 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 239 of the SDHB protein (p.Ser239Phe). This variant is present in population databases (rs201098090, gnomAD 0.01%). This missense change has been observed in individual(s) with metastatic paraganglioma (PMID: 18382370). ClinVar contains an entry for this variant (Variation ID: 412475). 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 SDHB protein function with a positive predictive value of 80%. 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. -

Gastrointestinal stromal tumor Uncertain:1
Mar 03, 2024
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1
Nov 01, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.S239F variant (also known as c.716C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 716. The serine at codon 239 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was identified in a patient with a personal history of metastatic paraganglioma (Klein RD et al. Diagn Mol Pathol, 2008 Jun;17:94-100). 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. -

Carney-Stratakis syndrome Uncertain:1
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.41
D
BayesDel_noAF
Pathogenic
0.58
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.99
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D
M_CAP
Pathogenic
0.53
D
MetaRNN
Pathogenic
0.92
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.9
H
PhyloP100
9.3
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.0
D
REVEL
Pathogenic
0.93
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0090
D
Polyphen
1.0
D
Vest4
0.93
MutPred
0.54
Loss of loop (P = 0.1242);
MVP
0.99
MPC
0.73
ClinPred
0.98
D
GERP RS
5.6
Varity_R
0.89
gMVP
0.98
Mutation Taster
=22/78
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: rs201098090; hg19: chr1-17349152; API