NM_003000.3(SDHB):c.418G>T (p.Val140Phe) AND Hereditary pheochromocytoma-paraganglioma

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 8, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000505378.6

Allele description [Variation Report for NM_003000.3(SDHB):c.418G>T (p.Val140Phe)]

NM_003000.3(SDHB):c.418G>T (p.Val140Phe)

Gene:

SDHB:succinate dehydrogenase complex iron sulfur subunit B [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_003000.3(SDHB):c.418G>T (p.Val140Phe)

HGVS:

NC_000001.11:g.17028605C>A
NG_012340.1:g.30566G>T
NM_003000.3:c.418G>TMANE SELECT
NP_002991.2:p.Val140Phe
NP_002991.2:p.Val140Phe
LRG_316t1:c.418G>T
LRG_316:g.30566G>T
LRG_316p1:p.Val140Phe
NC_000001.10:g.17355100C>A
NM_003000.2:c.418G>T
p.V140F

Protein change:

V140F; VAL140PHE

Links:

OMIM: 185470.0016; dbSNP: rs267607032

NCBI 1000 Genomes Browser:

rs267607032

Molecular consequence:

NM_003000.3:c.418G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hereditary pheochromocytoma-paraganglioma
Synonyms:: Hereditary Paraganglioma-Pheochromocytoma Syndromes; Hereditary Paragangliomas and Pheochromocytomas
Identifiers:: MONDO: MONDO:0017366; MedGen: C1708353

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599477	Section on Medical Neuroendocrinolgy, National Institutes of Health	no assertion criteria provided	Pathogenic	germline	research
SCV002572391	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 28, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 16912137, 17200167, 19215943, 19802898, 20583550, 20418362, 19189136, 19927285, 20213850, 20503330, 22270996 Citation Link,
SCV004822855	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 8, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28374168, 28503760, 29951630, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000599477

Section on Medical Neuroendocrinolgy, National Institutes of Health

no assertion criteria provided

Pathogenic

germline

research

SCV002572391

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 28, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

Citation Link,

SCV004822855

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 8, 2023)

germline

clinical testing

PubMed (15)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	3	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas.

Timmers HJ, Kozupa A, Eisenhofer G, Raygada M, Adams KT, Solis D, Lenders JW, Pacak K.

J Clin Endocrinol Metab. 2007 Mar;92(3):779-86. Epub 2007 Jan 2.

PubMed [citation]

PMID:: 17200167

Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD.

Ricketts CJ, Forman JR, Rattenberry E, Bradshaw N, Lalloo F, Izatt L, Cole TR, Armstrong R, Kumar VK, Morrison PJ, Atkinson AB, Douglas F, Ball SG, Cook J, Srirangalingam U, Killick P, Kirby G, Aylwin S, Woodward ER, Evans DG, Hodgson SV, Murday V, et al.

Hum Mutat. 2010 Jan;31(1):41-51. doi: 10.1002/humu.21136.

PubMed [citation]

PMID:: 19802898

See all PubMed Citations (19)

Details of each submission

From Section on Medical Neuroendocrinolgy, National Institutes of Health, SCV000599477.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided
2	not provided	not provided	not provided	not provided	research	not provided
3	not provided	not provided	not provided	not provided	research	not provided

Description

The penetrance of the disease in SDHB mutations carriers is not 100%, it is about 45-50%. There apparently are other factors contributing to disease development, however those are yet not known.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided
3	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002572391.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

Variant summary: SDHB c.418G>T (p.Val140Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251978 control chromosomes. c.418G>T has been reported in the literature in multiple individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome and a reduced penetrance in some families (examples, Brouwers_2006, Meyer-Rochow_2008, Trimmers_2007, Santiago_2010, Lodish_2010, Ricketts_2010, Majumdar_2010, Muth_2012, Prodanov_2009, Schimke_2010, Bayley_2010). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004822855.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (15)

Description

This missense variant replaces valine with phenylalanine at codon 140 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. This variant has been reported in over twenty individuals affected with hereditary paragangliomas/pheochromocytomas, including children (PMID: 16912137, 18840642, 19189136, 19215943, 19927285, 20418362, 20503330, 20583550, 25683602, 26236513, 27171833, 28503760, 29951630, 20503330). This variant has been shown to segregate with disease in two unrelated families (PMID: 20503330, 20583550). Multiple carrier individuals from one of these families were unaffected with SDHB-associated disease. One study has reported detection of this variant in 16 family members of 9 index patients, however, only 5 of these 16 family members were found to have paragangliomas/pheochromocytomas (PMID: 28374168). This study suggested that the penetrance of this variant is 50% at age 38. This variant has been identified in 3/251418 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		3	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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