NM_003002.4(SDHD):c.242C>T (p.Pro81Leu) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 15, 2021
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:: RCV000162448.15

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]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000212801	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Oct 15, 2021)	germline	clinical testing	PubMed (26) [See all records that cite these PMIDs] 10657297, 11156372, 11343322, 11391796, 11391798, 11897817, 12811540, 15479192, 19454582, 21937622, 22241717, 22290790, 23175444, 23433498, 23666964, 24102379, 24758185, 25014000, 25494863, 30050099, 30375904, 30484866, 30951038, 31194233, 32741965, 33748650 Citation Link,
SCV000698141	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 21, 2017)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19454582, 12811540, 21937622, 25695889, 23175444 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000212801

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Oct 15, 2021)

germline

clinical testing

PubMed (26)
[See all records that cite these PMIDs]

Citation Link,

SCV000698141

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 21, 2017)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma.

Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard CW 3rd, Cornelisse CJ, Devilee P, Devlin B.

Science. 2000 Feb 4;287(5454):848-51.

PubMed [citation]

PMID:: 10657297

Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma.

Gimm O, Armanios M, Dziema H, Neumann HP, Eng C.

Cancer Res. 2000 Dec 15;60(24):6822-5.

PubMed [citation]

PMID:: 11156372

See all PubMed Citations (27)

Details of each submission

From Ambry Genetics, SCV000212801.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (26)

Description

The p.P81L pathogenic mutation (also known as c.242C>T), located in coding exon 3 of the SDHD gene, results from a C to T substitution at nucleotide position 242. The proline at codon 81 is replaced by leucine, an amino acid with similar properties. This alteration has been described in numerous cases of familial paraganglioma/pheochromocytoma (PGL-PCC), multifocal PGL-PCC, and sporadic PGL-PCC (Baysal BE et al. Science. 2000 Feb;287(5454):848-51; Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37; Milunsky JM et al. Am. J. Med. Genet. 2001 May;100(4):311-4; Shulskaya MV et al. Int J Neurosci, 2018 Dec;128:1174-1179; Enríquez-Vega ME et al. Cir Cir, 2019;86:33-37; McCrary HC et al. JAMA Otolaryngol Head Neck Surg, 2019 07;145:641-646; Richter S et al. Genet Med, 2019 03;21:705-717; (Greenberg SE et al. Genet Med, 2020 12;22:2101-2107; Smith JD et al. OTO Open Mar;5:2473974X21995453) and has been shown to segregate with disease in PGL kindreds (Badenhop RF et al. Genes Chromosomes Cancer. 2001 Jul;31(3):255-63; Yeap PM et al. J. Clin. Endocrinol. Metab. 2011 Dec;96(12):E2009-13). A study consisting of 170 individuals with SDHD mutations, p.P81L carriers had a significantly lower risk for pheochromocytoma compared to other SDHD mutations (p=0.031) and presented almost exclusively with head/neck PGLs (Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). One study reported that this alteration results in an increased succinate:fumarate ratio and decreased SDHD enzymatic activity; although the alteration produced a false-negative result using succinate:fumarate ratio in a different study using enzymatic levels as a method for screening for SDH mutations in a tumor with loss of heterozygosity and reduced SDH activity (Canu L et al. J. Clin. Endorcinol. Metab. 2014 Jul;99(7):2321-6; Richter S et al. J. Clin. Endocrinol. Metab. 2014 Oct;99(10):3903-11). It is believed that both founder effects and mutation recurrence contribute to the prevalence of this alteration in North America (Baysal BE et al. J. Med. Genet. 2002 Mar;39(3):178-83; Astrom K et al. Hum. Genet. 2003 Aug;113(3):228-37). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698141.1

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

Description

Variant summary: The SDHD c.242C>T (p.Pro81Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense change that does not lie within a known functional domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 121894 control chromosomes tested in ExAC and published control cohorts. The variant has been reported in numerous patients, and has been found segregating with disease in families as well as in sporadic, non-familial cases. Based on the literature, the variant is considered a founder mutation and a well-known pathogenic allele. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, 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 26, 2024

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