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NM_004168.4(SDHA):c.1663+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 23, 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:
RCV002402720.1

Allele description

NM_004168.4(SDHA):c.1663+1G>A

Gene:
SDHA:succinate dehydrogenase complex flavoprotein subunit A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
5p15.33
Genomic location:
Preferred name:
NM_004168.4(SDHA):c.1663+1G>A
HGVS:
  • NC_000005.10:g.251104G>A
  • NG_012339.1:g.37864G>A
  • NM_001294332.2:c.1519+1G>A
  • NM_001330758.2:c.1552-3289G>A
  • NM_004168.4:c.1663+1G>AMANE SELECT
  • LRG_315t1:c.1663+1G>A
  • LRG_315:g.37864G>A
  • NC_000005.9:g.251219G>A
  • NM_004168.2:c.1663+1G>A
  • NM_004168.3:c.1663+1G>A
  • NM_004168.4:c.1663+1G>A
Links:
dbSNP: rs766667009
NCBI 1000 Genomes Browser:
rs766667009
Molecular consequence:
  • NM_001330758.2:c.1552-3289G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001294332.2:c.1519+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_004168.4:c.1663+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002708394Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(May 23, 2022) 		germlineclinical testing

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Details of each submission

From Ambry Genetics, SCV002708394.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided

Description

The c.1663+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 12 of the SDHA gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same donor site (c.1663+3G>C) has been detected in multiple individuals with a paraganglioma or gastrointestinal stromal tumor (Dwight T et al. Am J Surg Pathol, 2013 Feb;37:226-33; Ben Aim L et al. J Med Genet, 2019 08;56:513-520). c.1663+1G>A is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Mar 5, 2024