NM_003002.3(SDHD):c.242C>T (p.Pro81Leu) AND Hereditary Paraganglioma-Pheochromocytoma Syndromes

Clinical significance:Pathogenic (Last evaluated: Dec 4, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000020519.4

Allele description [Variation Report for NM_003002.3(SDHD):c.242C>T (p.Pro81Leu)]

NM_003002.3(SDHD):c.242C>T (p.Pro81Leu)

Gene:
SDHD:succinate dehydrogenase complex subunit D [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11q23.1
Genomic location:
Preferred name:
NM_003002.3(SDHD):c.242C>T (p.Pro81Leu)
HGVS:
  • NC_000011.10:g.112088939C>T
  • NG_012337.3:g.7093C>T
  • NM_001276503.1:c.169+966C>T
  • NM_001276506.1:c.242C>T
  • NM_003002.3:c.242C>T
  • NP_001263435.1:p.Pro81Leu
  • NP_002993.1:p.Pro81Leu
  • NC_000011.9:g.111959663C>T
  • NG_012337.2:g.7093C>T
  • NM_003002.1:c.242C>T
  • NM_003002.2:c.242C>T
  • NR_077060.1:n.326C>T
  • O14521:p.Pro81Leu
  • p.P81L
Protein change:
P81L; PRO81LEU
Links:
UniProtKB: O14521#VAR_010038; OMIM: 602690.0003; dbSNP: 80338844
NCBI 1000 Genomes Browser:
rs80338844
Molecular consequence:
  • NM_001276503.1:c.169+966C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_003002.3:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.1:n.326C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
3

Condition(s)

Name:
Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL-PCC)
Synonyms:
Hereditary Paragangliomas and Pheochromocytomas
Identifiers:
MedGen: C1708353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000040976GeneReviewsno assertion criteria providedpathologic
(Aug 30, 2012)
not providedcuration

SCV000599533Section on Medical Neuroendocrinolgy,National Institutes of Healthno assertion criteria providedPathogenicgermlineresearch

SCV000607172GenomeConnect, ClinGenno assertion providednot providedunknownphenotyping only

SCV000711451Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Dec 4, 2017)
germlineclinical testing

PubMed (9)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedresearch
not providednot providednot providednot providednot providednot providednot providednot providedliterature only
not providedgermlinenot provided33not providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedphenotyping only

Citations

PubMed

Pituitary adenoma with paraganglioma/pheochromocytoma (3PAs) and succinate dehydrogenase defects in humans and mice.

Xekouki P, Szarek E, Bullova P, Giubellino A, Quezado M, Mastroyannis SA, Mastorakos P, Wassif CA, Raygada M, Rentia N, Dye L, Cougnoux A, Koziol D, Sierra Mde L, Lyssikatos C, Belyavskaya E, Malchoff C, Moline J, Eng C, Maher LJ 3rd, Pacak K, Lodish M, et al.

J Clin Endocrinol Metab. 2015 May;100(5):E710-9. doi: 10.1210/jc.2014-4297. Epub 2015 Feb 19.

PubMed [citation]
PMID:
25695889
PMCID:
PMC4422891

Genetic testing in head and neck paraganglioma: who, what, and why?

Sridhara SK, Yener M, Hanna EY, Rich T, Jimenez C, Kupferman ME.

J Neurol Surg B Skull Base. 2013 Aug;74(4):236-40. doi: 10.1055/s-0033-1342924. Epub 2013 Apr 12.

PubMed [citation]
PMID:
24436918
PMCID:
PMC3715610
See all PubMed Citations (9)

Details of each submission

From GeneReviews, SCV000040976.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Section on Medical Neuroendocrinolgy,National Institutes of Health, SCV000599533.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearchnot provided
2not providednot providednot providednot providedresearchnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided
2germlineyesnot providednot providednot providednot providednot providednot providednot provided

From GenomeConnect, ClinGen, SCV000607172.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedphenotyping onlynot provided

Description

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine, SCV000711451.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (9)

Description

The p.Pro81Leu variant in SDHD has been reported in >25 individuals with paragangliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 2002, Mannelli 2006, Astrom 2003). This variant, along with loss of heterozygosity, has also been found as a somatic change in the tumor of an individual with an isolated pheochromocytoma (Gimm 2000). It has also been reported by other clinical laboratories in ClinVar (Variation ID 6896). This variant has also been identified in 3/126674 of European chromosomes by the Genome Aggregation Database (gnomAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low enough to be consistent with the frequency of hereditary PGL/PCC syndrome in the general population. In summary, this variant meets criteria to be classified as pathogenic for hereditary paraganglioma-pheochromocytoma syndrome in an autosomal dominant manner based upon segregation studies and presence in multiple affected individuals. ACMG/AMP Criteria applied: PS4, PP1_Strong (Richards 2015).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided3not provided

Last Updated: Apr 12, 2018