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NM_003000.3(SDHB):c.287-1G>C AND Hereditary pheochromocytoma-paraganglioma

Germline classification:
Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:
Jan 4, 2024
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:
RCV000037719.11

Allele description [Variation Report for NM_003000.3(SDHB):c.287-1G>C]

NM_003000.3(SDHB):c.287-1G>C

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.287-1G>C
HGVS:
  • NC_000001.11:g.17028737C>G
  • NG_012340.1:g.30434G>C
  • NM_001407361.1:c.287-1G>C
  • NM_003000.3:c.287-1G>CMANE SELECT
  • LRG_316t1:c.287-1G>C
  • LRG_316:g.30434G>C
  • NC_000001.10:g.17355232C>G
  • NM_003000.2:c.287-1G>C
  • c.287-1G>C
Links:
dbSNP: rs397516833
NCBI 1000 Genomes Browser:
rs397516833
Molecular consequence:
  • NM_001407361.1:c.287-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
  • NM_003000.3:c.287-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061381Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Dec 6, 2012)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000599494Section on Medical Neuroendocrinolgy, National Institutes of Health
no assertion criteria provided
Pathogenicgermlineresearch

SCV001821468Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Aug 8, 2021)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV004831695All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 4, 2024)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlinenot provided11not providednot providednot providedclinical testing
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

LaDuca H, Farwell KD, Vuong H, Lu HM, Mu W, Shahmirzadi L, Tang S, Chen J, Bhide S, Chao EC.

PLoS One. 2017;12(2):e0170843. doi: 10.1371/journal.pone.0170843.

PubMed [citation]
PMID:
28152038
PMCID:
PMC5289469
See all PubMed Citations (15)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061381.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The 287-1G>C variant in SDHB has been reported in one individual with paragangli oma and segregated with disease in one affected relative in that family (Timmers 2007). This variant has also been identified in a benign paraganglioma sample ( Klein 2008). This variant occurs in the invariant region (+/- 1,2) of the splic e consensus sequence and is predicted to cause altered splicing leading to an ab normal or absent protein. In summary, the 287-1G>C variant is likely pathogenic, though additional studies are required to fully establish its clinical signific ance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Section on Medical Neuroendocrinolgy, National Institutes of Health, SCV000599494.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001821468.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: SDHB c.287-1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splice acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251204 control chromosomes. c.287-1G>C has been reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Timmers_2007, Jafri_2013, Fishbein_2013, Del Forno_2016, LaDuca_2017, Rinelli_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From All of Us Research Program, National Institutes of Health, SCV004831695.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (11)

Description

This variant disrupts a canonical splice site and is predicted to result in abnormal splicing. Aberrant splicing and/or loss of function is an established mechanism of disease. This prediction has not been confirmed by functional studies. A different variant at the same splice site has been reported in association with disease and is independently classified as likely pathogenic or pathogenic. This variant has been reported in multiple individuals with paraganglioma (PMID: 17200167, 18382370, 23072324, 25371406, 36786389, 28179334, 27549546, 30050099, 28374168, 36387130). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Jul 15, 2024