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NM_003002.4(SDHD):c.416T>G (p.Leu139Arg) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jun 9, 2022
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV002532294.10

Allele description [Variation Report for NM_003002.4(SDHD):c.416T>G (p.Leu139Arg)]

NM_003002.4(SDHD):c.416T>G (p.Leu139Arg)

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.416T>G (p.Leu139Arg)
HGVS:
  • NC_000011.10:g.112094906T>G
  • NG_012337.3:g.13060T>G
  • NM_001276503.2:c.*13T>G
  • NM_001276504.2:c.299T>G
  • NM_001276506.2:c.*114T>G
  • NM_003002.4:c.416T>GMANE SELECT
  • NP_001263433.1:p.Leu100Arg
  • NP_002993.1:p.Leu139Arg
  • LRG_9t1:c.416T>G
  • LRG_9:g.13060T>G
  • LRG_9p1:p.Leu139Arg
  • NC_000011.9:g.111965630T>G
  • NM_003002.3:c.416T>G
  • NR_077060.2:n.505T>G
Protein change:
L100R
Links:
dbSNP: rs80338847
NCBI 1000 Genomes Browser:
rs80338847
Molecular consequence:
  • NM_001276503.2:c.*13T>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001276506.2:c.*114T>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_001276504.2:c.299T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.416T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.505T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Carney-Stratakis syndrome
Synonyms:
Paraganglioma and gastric stromal sarcoma; Paraganglioma and gastrointestinal stromal tumor; Paraganglioma and GIST; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0011740; MedGen: C1847319; Orphanet: 97286; OMIM: 606864
Name:
Pheochromocytoma
Synonyms:
Chromaffinoma; Chromaffin paraganglioma; Chromaffin tumor; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0008233; MedGen: C0031511; Orphanet: 29072; OMIM: 171300; Human Phenotype Ontology: HP:0002666
Name:
Paragangliomas with sensorineural hearing loss
Identifiers:
MedGen: C1868633
Name:
Cowden syndrome 3 (CWS3)
Identifiers:
MONDO: MONDO:0014045; MedGen: CN166604; Orphanet: 201

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000823868Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Jun 9, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Frequent germ-line succinate dehydrogenase subunit D gene mutations in patients with apparently sporadic parasympathetic paraganglioma.

Dannenberg H, Dinjens WN, Abbou M, Van Urk H, Pauw BK, Mouwen D, Mooi WJ, de Krijger RR.

Clin Cancer Res. 2002 Jul;8(7):2061-6.

PubMed [citation]
PMID:
12114404

High prevalence of founder mutations of the succinate dehydrogenase genes in the Netherlands.

Hensen EF, van Duinen N, Jansen JC, Corssmit EP, Tops CM, Romijn JA, Vriends AH, van der Mey AG, Cornelisse CJ, Devilee P, Bayley JP.

Clin Genet. 2012 Mar;81(3):284-8. doi: 10.1111/j.1399-0004.2011.01653.x. Epub 2011 Mar 15.

PubMed [citation]
PMID:
21348866
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000823868.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 139 of the SDHD protein (p.Leu139Arg). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu139 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12114404, 21348866, 25758995). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 573651). This variant has not been reported in the literature in individuals affected with SDHD-related conditions. This variant is not present in population databases (gnomAD no frequency).

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

Last Updated: Sep 29, 2024