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

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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:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000040976	GeneReviews	no assertion criteria provided	pathologic (Aug 30, 2012)	not provided	curation
SCV000599533	Section on Medical Neuroendocrinolgy,National Institutes of Health	no assertion criteria provided	Pathogenic	germline	research
SCV000607172	GenomeConnect, ClinGen	no assertion provided	not provided	unknown	phenotyping only
SCV000711451	Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	criteria provided, single submitter LMM Criteria	Pathogenic (Dec 4, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25695889, 24436918, 21937622, 11897817, 17102085, 23175444, 11156372, 12811540, 24033266

Summary from all submissions

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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	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	not provided	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	phenotyping 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

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

Description

Converted during submission to Pathogenic.

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

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

#	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

#	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
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GenomeConnect, ClinGen, SCV000607172.1

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

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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical 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).

#	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		3	not provided	3	not provided

Last Updated: Apr 12, 2018

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