rs948484408

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5

The NM_003000.3(SDHB):c.761C>T(p.Pro254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,608 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P254R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 7.38

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-17022612-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2947609.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 1-17022612-G-A is Pathogenic according to our data. Variant chr1-17022612-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412459.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr1-17022612-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3 link	c.761C>T	p.Pro254Leu	missense_variant	Exon 7 of 8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 link	c.707C>T	p.Pro236Leu	missense_variant	Exon 7 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 link	c.761C>T	p.Pro254Leu	missense_variant	Exon 7 of 8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461608

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Mar 17, 2022

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P254L variant (also known as c.761C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 761. The proline at codon 254 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in multiple individuals with paragangliomas (Lima J et al. J Clin Endocrinol Metab, 2007 Dec;92:4853-64; Neumann HP et al. Cancer Res, 2009 Apr;69:3650-6; Burnichon N et al. J Clin Endocrinol Metab, 2009 Aug;94:2817-27; Hermsen MA et al. Cell Oncol, 2010 Jan;32:275-83; Rijken JA et al. BJS Open, 2018 Apr;2:62-69; Bernardo-Castiñeira C et al. Head Neck, 2019 01;41:79-91; Donato S et al. Endocrine, 2019 08;65:408-415). Based on internal structural analysis, p.P254L is considered deleterious (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is also considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Mar 17, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2_Supporting, PP3_Moderate c.761C>T, located in exon 7 of the SDHB gene, is predicted to result in the substitution of proline by leucine at codon 254, p.(Pro254Leu). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.981) for this variant suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3_Moderate). To our knowledge functional studies have not been reported for this variant. It has been reported in ClinVar (1x uncertain significance, 1x likely pathogenic) and LOVD (3x uncertain significance, 1x likely pathogenic) databases. It has been identified in multiple affected individual with paraganglioma (PMID: 17848412, 19454582, 20208144, 29951630 and internal data)(PS4). Based on currently available information, c.761C>T is classified as a likely pathogenic variant according to ACMG guidelines. -

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4

Uncertain:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 254 of the SDHB protein (p.Pro254Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with paraganglioma (PGL) and/or paraganglioma-pheochromocytoma syndromes (PMID: 17848412, 19351833, 19454582, 20208144, 29951630, 34750850, 34906457). ClinVar contains an entry for this variant (Variation ID: 412459). 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%. This variant disrupts the p.Pro254 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.7

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.3

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.94

Loss of ubiquitination at K255 (P = 0.0372);

MVP

1.0

MPC

0.70

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.96

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over