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NM_003002.4(SDHD):c.275A>T (p.Asp92Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 17, 2017
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:
RCV000569878.10

Allele description [Variation Report for NM_003002.4(SDHD):c.275A>T (p.Asp92Val)]

NM_003002.4(SDHD):c.275A>T (p.Asp92Val)

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.275A>T (p.Asp92Val)
HGVS:
  • NC_000011.10:g.112088972A>T
  • NG_012337.3:g.7126A>T
  • NG_033145.1:g.2827T>A
  • NM_001276503.2:c.169+999A>T
  • NM_001276504.2:c.158A>T
  • NM_001276506.2:c.275A>T
  • NM_003002.4:c.275A>TMANE SELECT
  • NP_001263433.1:p.Asp53Val
  • NP_001263435.1:p.Asp92Val
  • NP_002993.1:p.Asp92Val
  • LRG_9t1:c.275A>T
  • LRG_9:g.7126A>T
  • LRG_9p1:p.Asp92Val
  • NC_000011.9:g.111959696A>T
  • NM_003002.2:c.275A>T
  • NM_003002.3:c.275A>T
  • NR_077060.2:n.310A>T
Protein change:
D53V
Links:
dbSNP: rs786205436
NCBI 1000 Genomes Browser:
rs786205436
Molecular consequence:
  • NM_001276503.2:c.169+999A>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001276504.2:c.158A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001276506.2:c.275A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003002.4:c.275A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_077060.2:n.310A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000664532Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Oct 17, 2017) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From Ambry Genetics, SCV000664532.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The p.D92V likely pathogenic variant (also known as c.275A>T), located in coding exon 3 of the SDHD gene, results from an A to T substitution at nucleotide position 275. The aspartic acid at codon 92 is replaced by valine, an amino acid with highly dissimilar properties. Though this exact alteration has not been reported in the literature, a mutation at the same codon, p.D92Y, is recognized as a Dutch founder mutation and has been reported in multiple individuals with paraganglioma-pheochromocytoma syndrome (PGL/PCC) (Hensen EF et al. Clin. Genet. 2012 Mar;81(3):284-8). Another mutation at the same codon, p.D92G, has been reported in a homozygous individual who passed away in infancy from severe mitochondrial complex II deficiency (Alston CL et al. Hum. Genet. 2015 Aug;134(8):869-79). Structural analysis of the p.D92V alteration suggests that this variant disrupts the folding of SDHD to a higher degree than the known pathogenic variants p.D92Y and p.D92G at the same position, leading either to reduction or loss of protein function (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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

Last Updated: Oct 8, 2024