NM_003000.3(SDHB):c.418G>T (p.Val140Phe) AND Paragangliomas 4

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Apr 24, 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:: RCV000013634.38

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]

Condition(s)

Name:: Paragangliomas 4 (PPGL4)
Synonyms:: CAROTID BODY TUMORS AND MULTIPLE EXTRAADRENAL PHEOCHROMOCYTOMAS; Pheochromocytoma, extraadrenal and cervical paraganglioma; Paragangliomas, hereditary extraadrenal; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007273; MedGen: C1861848; Orphanet: 29072; OMIM: 115310

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000033881	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2010)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 20503330, 490809
SCV000488516	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Apr 28, 2016)	unknown	clinical testing	PubMed (9) [See all records that cite these PMIDs] 22270996, 19927285, 19576851, 19189136, 18840642, 19802898, 20503330, 23512077, 16912137 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000596999	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 7, 2015)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004045432	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Apr 24, 2023)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20503330, 20583550, 30050099, 16912137, 19576851 Citation Link,
SCV004362276	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 25, 2022)	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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Neuroblastoma, pheochromocytoma, and renal cell carcinoma. Occurrence in a single patient.

Fairchild RS, Kyner JL, Hermreck A, Schimke RN.

JAMA. 1979 Nov 16;242(20):2210-1.

PubMed [citation]

PMID:: 490809

Prevalence of germline mutations in patients with pheochromocytoma or abdominal paraganglioma and sporadic presentation: a population-based study in Western Sweden.

Muth A, Abel F, Jansson S, Nilsson O, Ahlman H, Wängberg B.

World J Surg. 2012 Jun;36(6):1389-94. doi: 10.1007/s00268-012-1430-6.

PubMed [citation]

PMID:: 22270996
PMCID:: PMC3348434

See all PubMed Citations (21)

Details of each submission

From OMIM, SCV000033881.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 2 sibs with paragangliomas (PPGL4; 115310), Schimke et al. (2010) identified a heterozygous 418G-T transversion in the SDHB gene, resulting in a val140-to-phe (V140F) substitution. The 55-year-old sister and 49-year-old brother both had paraspinal paragangliomas. The mutation was also found in their unaffected 76-year-old mother, suggesting decreased penetrance or a 'leaky' mutation. The family was of note because a deceased sib had neuroblastoma as an infant, metastatic extraadrenal sympathetic paragangliomas reminiscent of pheochromocytoma as a young adult, and renal cell carcinoma as an adult; this patient had been previously reported by Fairchild et al. (1979) as having unique occurrence of these cancers. In addition, a first cousin of these sibs had died from metastatic renal cell carcinoma and had a history of a benign paraaortic PGL. Schimke et al. (2010) noted the importance of family history in elucidating the etiology of this inherited disorder.

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

From Counsyl, SCV000488516.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

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

From Genetic Services Laboratory, University of Chicago, SCV000596999.1

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

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

From Myriad Genetics, Inc., SCV004045432.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:20503330, 20583550, 30050099, 16912137, 19576851]. This variant is expected to disrupt protein structure [Myriad internal data].

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

From Color Diagnostics, LLC DBA Color Health, SCV004362276.1

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

Last Updated: Oct 13, 2024

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