NM_003002.4(SDHD):c.242C>T (p.Pro81Leu) AND Hereditary pheochromocytoma-paraganglioma

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Dec 6, 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:: RCV000020519.21

Allele description [Variation Report for NM_003002.4(SDHD):c.242C>T (p.Pro81Leu)]

NM_003002.4(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_003002.4(SDHD):c.242C>T (p.Pro81Leu)

HGVS:

NC_000011.10:g.112088939C>T
NG_012337.3:g.7093C>T
NG_033145.1:g.2860G>A
NM_001276503.2:c.169+966C>T
NM_001276504.2:c.125C>T
NM_001276506.2:c.242C>T
NM_003002.4:c.242C>TMANE SELECT
NP_001263433.1:p.Pro42Leu
NP_001263435.1:p.Pro81Leu
NP_002993.1:p.Pro81Leu
LRG_9t1:c.242C>T
LRG_9:g.7093C>T
LRG_9p1:p.Pro81Leu
NC_000011.9:g.111959663C>T
NM_001276506.1:c.242C>T
NM_003002.1:c.242C>T
NM_003002.2:c.242C>T
NM_003002.3:c.242C>T
NR_077060.2:n.277C>T
O14521:p.Pro81Leu
p.P81L

Protein change:

P42L; PRO81LEU

Links:

UniProtKB: O14521#VAR_010038; OMIM: 602690.0003; dbSNP: rs80338844

NCBI 1000 Genomes Browser:

rs80338844

Molecular consequence:

NM_001276503.2:c.169+966C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001276504.2:c.125C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001276506.2:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003002.4:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_077060.2:n.277C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV000040976	GeneReviews	no classification provided	not provided	unknown	literature only	PubMed (8) [See all records that cite these PMIDs] 10657297, 11156372, 11343322, 11391796, 11391798, 11897817, 12811540, 20301715
SCV000599533	Section on Medical Neuroendocrinolgy, National Institutes of Health	no assertion criteria provided	Pathogenic	germline	research
SCV000607172	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV000711451	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Sep 21, 2016)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 25695889, 24436918, 21937622, 11897817, 17102085, 23175444, 11156372, 12811540, 24033266
SCV004814331	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2023)	germline	clinical testing	PubMed (34) [See all records that cite these PMIDs] 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21348866, 21937622, 22290790, 22575350, 23433498, 23666964, 24102379, 24436918, 24758185, 25014000, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822, 25741868

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	not provided	3	3	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	6	not provided	not provided	108544	not provided	clinical testing, research
not provided	unknown	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	phenotyping only

Citations

PubMed

Hereditary Paraganglioma-Pheochromocytoma Syndromes.

Else T, Greenberg S, Fishbein L.

2008 May 21 [updated 2023 Sep 21]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(®) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

PubMed [citation]

PMID:: 20301715

Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome.

Panizza E, Ercolino T, Mori L, Rapizzi E, Castellano M, Opocher G, Ferrero I, Neumann HP, Mannelli M, Goffrini P.

Hum Mol Genet. 2013 Feb 15;22(4):804-15. doi: 10.1093/hmg/dds487. Epub 2012 Nov 21.

PubMed [citation]

PMID:: 23175444

See all PubMed Citations (38)

Details of each submission

From GeneReviews, SCV000040976.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, Mass General Brigham Personalized Medicine, SCV000711451.2

#	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 paragan gliomas and/or pheochromocytomas (PGL/PCC), segregated with disease in at least 16 relatives from 7 families (Xekouki 2015, Sridhara 2013, Yeap 2011, Baysal 200 2, 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 i solated pheochromocytoma (Gimm 2000). It has also been reported by other clinica l laboratories in ClinVar (Variation ID 6896). This variant has also been identi fied in 3/126674 of European chromosomes by the Genome Aggregation Database (gno mAD, http:/gnomad.broadinstitute.org; dbSNP rs80338844). This frequency is low e nough 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 autosoma l dominant manner based upon segregation studies and presence in multiple affect ed 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

From All of Us Research Program, National Institutes of Health, SCV004814331.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (34)

Description

This missense variant replaces proline with leucine at codon 81 of the SDHD 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). Functional studies have shown that succinate dehydrogenase complexes with this SDHD variant exhibit lower SDH enzyme activity observed via a higher succinate to fumarate metabolite ratio (PMID: 24758185, 25014000, 30050099). This variant has been reported in numerous individuals affected with pheochromocytoma/paraganglioma (PMID: 8981955, 10657297, 11343322, 11391796, 11391798, 11897817, 12811540, 14974914, 15235042, 15328326, 15479192, 17102085, 19454582, 21937622, 21348866, 22290790, 22575350, 23433498, 23666964, 24436918, 24102379, 25326637, 25494863, 25695889, 29386252, 29625052, 29681642, 29777207, 30050099, 30375904, 31492822). It has been also shown that this variant segregates with disease (PMID: 8981955, 11391796, 11897817, 15479192, 22575350, 25695889). This variant has been identified in 6/282810 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		6	not provided	not provided	not provided

Last Updated: Oct 26, 2024

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