NM_003002.4(SDHD):c.242C>T (p.Pro81Leu) AND Paragangliomas 1

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Mar 29, 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:: RCV000007303.19

Allele description

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:: Paragangliomas 1
Synonyms:: Paragangliomata; Glomus tumors familial 1; Paraganglioma - glomus jugulare; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008192; MedGen: C3494181; Orphanet: 29072; OMIM: 168000

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027499	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2003)	unknown	literature only	PubMed (6) [See all records that cite these PMIDs] 10657297, 11343322, 11391796, 12811540, 11897817, 11156372
SCV000255463	UCLA Clinical Genomics Center, UCLA - CES	criteria provided, single submitter (Lee et al. (JAMA. 2014))	Pathogenic (Jan 21, 2014)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000782285	Center for Human Genetics, Inc, Center for Human Genetics, Inc	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175324	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 10657297, 11391796, 11897812, 19454582, 21348866, 21937622, 23433498, 25494863, 29386252, 25741868
SCV004362302	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 27, 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
SCV004808089	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	not provided	not provided	not provided	not provided	not provided	not provided	literature only
European Caucasian	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

CP27 localization in the dental lamina basement membrane and in the stellate reticulum of developing teeth.

Diekwisch TG, Luan X, McIntosh JE.

J Histochem Cytochem. 2002 Apr;50(4):583-6.

PubMed [citation]

PMID:: 11897812

See all PubMed Citations (36)

Details of each submission

From OMIM, SCV000027499.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (6)

Description

Paragangliomas 1 with or without Sensorneural Hearing Loss

In 5 families with autosomal dominant hereditary paraganglioma (PGL1; 168000), Baysal et al. (2000) identified a C-to-T transition in the SDHD gene, resulting in a pro81-to-leu (P81L) substitution. The proline at position 81 is conserved in human, Bos taurus, Ascaris, and Caenorhabditis elegans.

Milunsky et al. (2001) found the pro81-to-leu mutation in 3 of 7 families with hereditary paragangliomas. Since this mutation results in the elimination of a normally occurring restriction endonuclease site (MspI), Milunsky et al. (2001) developed a restriction enzyme assay to screen for this mutation.

Badenhop et al. (2001) found the P81L mutation in an individual with sensorineural deafness in association with paragangliomas, as well as in 3 other family members who had only paragangliomas.

In an analysis of 23 families with paragangliomas-1, Astrom et al. (2003) identified the P81L mutation in 14 (approximately 61%). P81L had been implicated both as a founder and as a recurrent mutation among U.S. families (Baysal et al., 2002). Haplotype analyses of the 14 P81L carrier families indicated that 5 lacked the founder haplotype, suggesting independent origin.

Pheochromocytoma, Somatic

Gimm et al. (2000) found the P81L mutation in the heterozygous state as a somatic mutation in tumor tissue from a patient with sporadic (nonfamilial) pheochromocytoma (see 171300). Flanking markers also showed loss of heterozygosity.

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

From UCLA Clinical Genomics Center, UCLA - CES, SCV000255463.2

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

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

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782285.1

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

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

From Genetics and Molecular Pathology, SA Pathology, SCV004175324.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The SDHD c.242C>T variant is classified as Pathogenic (PM2, PP3, PP1_Strong) The SDHD c.242C>T variant is a single nucleotide change in exon 3/4 of the SDHD gene, which is predicted to change the amino acid proline at position 81 in the protein to leucine. The variant has been reported in many patients with paraganglioma and has been suggested to be a founder variant (PMID:10657297, 11391796, 11897812, 19454582,21348866, 23433498, 25494863) (PS4). The variant is rare in population databases (gnomAD allele frequency = 0.0013%; 2 het and 0 hom in 152182 sequenced alleles; highest frequency = 0.0029%, Non-Finnish European population) (PM2). This variant co-segregates with disease (PMID:21937622, 10657297, 29386252) (PP1_strong). Computational predictions strongly support a deleterious effect on the gene or gene product (PP3). The variant has been reported in dbSNP (rs80338844) and as disease causing in the HGMD database (CM000207). It has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 6896).

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

From Color Diagnostics, LLC DBA Color Health, SCV004362302.1

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004808089.1

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

#	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: Apr 20, 2024

ClinVar

Relating variation to medicine