NM_003002.4(SDHD):c.305A>C (p.His102Pro) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Jul 2, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001222676.2

Allele description [Variation Report for NM_003002.4(SDHD):c.305A>C (p.His102Pro)]

NM_003002.4(SDHD):c.305A>C (p.His102Pro)

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.305A>C (p.His102Pro)
HGVS:
  • NC_000011.10:g.112089002A>C
  • NG_012337.3:g.7156A>C
  • NG_033145.1:g.2797T>G
  • NM_001276503.2:c.169+1029A>C
  • NM_001276504.2:c.188A>C
  • NM_001276506.2:c.305A>C
  • NM_003002.4:c.305A>CMANE SELECT
  • NP_001263433.1:p.His63Pro
  • NP_001263435.1:p.His102Pro
  • NP_002993.1:p.His102Pro
  • LRG_9t1:c.305A>C
  • LRG_9:g.7156A>C
  • LRG_9p1:p.His102Pro
  • NC_000011.9:g.111959726A>C
  • NM_003002.3:c.305A>C
  • NR_077060.2:n.340A>C
Protein change:
H102P
Molecular consequence:
  • NM_001276503.2:c.169+1029A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001276504.2:c.188A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276506.2:c.305A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.305A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.340A>C - 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 1 (PGL1)
Synonyms:
PARAGANGLIOMA, CAROTID BODY; PARAGANGLIOMAS, FAMILIAL NONCHROMAFFIN, 1; PGL 1; See all synonyms [MedGen]
Identifiers:
MedGen: C1868633; Orphanet: 29072; OMIM: 168000
Name:
Cowden syndrome 3 (CWS3)
Identifiers:
MONDO: MONDO:0014045; MedGen: CN166604; Orphanet: 201

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001394789Invitaecriteria provided, single submitter
Uncertain significance
(Jul 2, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect.

Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE.

Hum Genet. 2003 Aug;113(3):228-37. Epub 2003 Jun 17.

PubMed [citation]
PMID:
12811540
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001394789.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces histidine with proline at codon 102 of the SDHD protein (p.His102Pro). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with clinical features of SDHD-related hereditary paraganglioma-pheochromocytoma syndrome (PMID: 19454582, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.His102 amino acid residue in SDHD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10657297, 12811540, 19454582, 22025150, 22241717, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Oct 7, 2021

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