NM_003002.4(SDHD):c.3G>C (p.Met1Ile) AND Hereditary Paraganglioma-Pheochromocytoma Syndromes

Clinical significance:Pathogenic (Last evaluated: Jul 21, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000020522.4

Allele description [Variation Report for NM_003002.4(SDHD):c.3G>C (p.Met1Ile)]

NM_003002.4(SDHD):c.3G>C (p.Met1Ile)

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.3G>C (p.Met1Ile)
Other names:
p.Met1?
HGVS:
  • NC_000011.10:g.112086910G>C
  • NG_012337.3:g.5064G>C
  • NG_033145.1:g.4889C>G
  • NM_001276503.2:c.3G>C
  • NM_001276504.2:c.3G>C
  • NM_001276506.2:c.3G>C
  • NM_003002.4:c.3G>CMANE SELECT
  • NP_001263432.1:p.Met1Ile
  • NP_001263433.1:p.Met1Ile
  • NP_001263435.1:p.Met1Ile
  • NP_002993.1:p.Met1Ile
  • LRG_9t1:c.3G>C
  • LRG_9:g.5064G>C
  • LRG_9p1:p.Met1Ile
  • NC_000011.9:g.111957634G>C
  • NM_003002.1:c.3G>C
  • NM_003002.2:c.3G>C
  • NM_003002.3:c.3G>C
  • NR_077060.2:n.38G>C
Protein change:
M1I; MET1ILE
Links:
OMIM: 602690.0015; dbSNP: rs80338842
NCBI 1000 Genomes Browser:
rs80338842
Molecular consequence:
  • NM_001276503.2:c.3G>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001276504.2:c.3G>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001276506.2:c.3G>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_003002.4:c.3G>C - initiatior codon variant - [Sequence Ontology: SO:0001582]
  • NM_001276503.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276504.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276506.2:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.3G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.38G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
3

Condition(s)

Name:
Hereditary Paraganglioma-Pheochromocytoma Syndromes (PGL-PCC)
Synonyms:
Hereditary Paragangliomas and Pheochromocytomas
Identifiers:
MONDO: MONDO:0017366; MedGen: C1708353

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000040979GeneReviewsno assertion criteria providedpathologic
(Aug 30, 2012)
not providedcuration

SCV000967764Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Jul 21, 2019)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown33not providednot providednot providedclinical testing
not providednot providednot providednot providednot providednot providednot providednot providedcuration

Citations

PubMed

Novel mutations in the SDHD gene in pedigrees with familial carotid body paraganglioma and sensorineural hearing loss.

Badenhop RF, Cherian S, Lord RS, Baysal BE, Taschner PE, Schofield PR.

Genes Chromosomes Cancer. 2001 Jul;31(3):255-63.

PubMed [citation]
PMID:
11391796

Hereditary paraganglioma due to the SDHD M1I mutation in a second Chinese family: a founder effect?

Lee SC, Chionh SB, Chong SM, Taschner PE.

Laryngoscope. 2003 Jun;113(6):1055-8.

PubMed [citation]
PMID:
12782822
See all PubMed Citations (12)

Details of each submission

From GeneReviews, SCV000040979.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

Converted during submission to Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot providednot providednot providedAssert pathogenicitynot providednot providednot providednot provided

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000967764.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (12)

Description

The c.3G>C (p.Met1?) variant in SDHD has been identified to be a Chinese founder variant and has been reported in at least 13 Chinese individuals with hereditary paragangliomas and/or pheochromocytomas (PGL/PCC), segregating with disease in at least 10 relatives in these families (Badenhop 2001, Lee 2003, Ma 2007, Zha 2011, Wang 2012, Zhu 2015). This variant has also been reported by other clinical laboratories in Clinvar (Variation ID: 6906) and was absent from large population studies. The p.Met1? variant alters the evolutionary conserved initiation codon of the SDHD gene and is predicted to disrupt translation. The precise effect on the protein cannot be predicted, as this variant may lead to no protein synthesis or the activation of an upstream translation initiation codon, resulting in an aberrant protein. Additionally, other variants at this position, resulting in the same impact on the protein, have been reported in individuals with PGL/PCC (Burnichon 2009, Cascon 2009, Neumayer 2007, Piccini 2012, Riemann 2004). Heterozygous loss of function of the SDHD gene is an established disease mechanism in individuals with hereditary PGL/PCC. In summary, this variant meets criteria to be classified as pathogenic for hereditary PGL/PCC in an autosomal dominant manner based upon multiple occurrences in affected individuals, segregation studies, absence from the general population, and the predicted impact on protein. ACMG/AMP criteria applied: PS4; PVS1_Moderate, PM2, PP1_Strong.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided3not provided3not provided

Last Updated: Nov 27, 2021

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