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NM_003002.4(SDHD):c.274G>T (p.Asp92Tyr) AND multiple conditions

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 21, 2023
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:
RCV002512869.9

Allele description [Variation Report for NM_003002.4(SDHD):c.274G>T (p.Asp92Tyr)]

NM_003002.4(SDHD):c.274G>T (p.Asp92Tyr)

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.274G>T (p.Asp92Tyr)
HGVS:
  • NC_000011.10:g.112088971G>T
  • NG_012337.3:g.7125G>T
  • NG_033145.1:g.2828C>A
  • NM_001276503.2:c.169+998G>T
  • NM_001276504.2:c.157G>T
  • NM_001276506.2:c.274G>T
  • NM_003002.4:c.274G>TMANE SELECT
  • NP_001263433.1:p.Asp53Tyr
  • NP_001263435.1:p.Asp92Tyr
  • NP_002993.1:p.Asp92Tyr
  • LRG_9t1:c.274G>T
  • LRG_9:g.7125G>T
  • LRG_9p1:p.Asp92Tyr
  • NC_000011.9:g.111959695G>T
  • NM_003002.1:c.274G>T
  • NM_003002.2:c.274G>T
  • NM_003002.3:c.274G>T
  • NR_077060.2:n.309G>T
  • O14521:p.Asp92Tyr
Protein change:
D53Y; ASP92TYR
Links:
UniProtKB: O14521#VAR_010039; OMIM: 602690.0004; dbSNP: rs80338845
NCBI 1000 Genomes Browser:
rs80338845
Molecular consequence:
  • NM_001276503.2:c.169+998G>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001276504.2:c.157G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276506.2:c.274G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.274G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.309G>T - 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 (PGL1)
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
SCV000287820Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jul 21, 2023) 		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

A recessive homozygous p.Asp92Gly SDHD mutation causes prenatal cardiomyopathy and a severe mitochondrial complex II deficiency.

Alston CL, Ceccatelli Berti C, Blakely EL, Oláhová M, He L, McMahon CJ, Olpin SE, Hargreaves IP, Nolli C, McFarland R, Goffrini P, O'Sullivan MJ, Taylor RW.

Hum Genet. 2015 Aug;134(8):869-79. doi: 10.1007/s00439-015-1568-z. Epub 2015 May 26.

PubMed [citation]
PMID:
26008905
PMCID:
PMC4495259

The Dutch founder mutation SDHD.D92Y shows a reduced penetrance for the development of paragangliomas in a large multigenerational family.

Hensen EF, Jansen JC, Siemers MD, Oosterwijk JC, Vriends AH, Corssmit EP, Bayley JP, van der Mey AG, Cornelisse CJ, Devilee P.

Eur J Hum Genet. 2010 Jan;18(1):62-6. doi: 10.1038/ejhg.2009.112.

PubMed [citation]
PMID:
19584903
PMCID:
PMC2987152
See all PubMed Citations (4)

Details of each submission

From Invitae, SCV000287820.5

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

Description

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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this missense change affects SDHD function (PMID: 26008905). ClinVar contains an entry for this variant (Variation ID: 6897). This missense change has been observed in individual(s) with paraganglioma and pheochromocytoma (PMID: 19584903, 21348866). It is commonly reported in individuals of Dutch ancestry (PMID: 19584903, 21348866). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 92 of the SDHD protein (p.Asp92Tyr).

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

Last Updated: Apr 20, 2024