NM_004168.4(SDHA):c.554dup (p.Ala186fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 28, 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:: RCV002350731.2

Allele description [Variation Report for NM_004168.4(SDHA):c.554dup (p.Ala186fs)]

NM_004168.4(SDHA):c.554dup (p.Ala186fs)

Gene:

SDHA:succinate dehydrogenase complex flavoprotein subunit A [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

5p15.33

Genomic location:

Preferred name:

NM_004168.4(SDHA):c.554dup (p.Ala186fs)

HGVS:

NC_000005.10:g.225980dup
NG_012339.1:g.12740dup
NM_001294332.2:c.410dup
NM_001330758.2:c.554dup
NM_004168.4:c.554dupMANE SELECT
NP_001281261.1:p.Ala138fs
NP_001317687.1:p.Ala186fs
NP_004159.2:p.Ala186fs
LRG_315t1:c.554dup
LRG_315:g.12740dup
LRG_315p1:p.Ala186fs
NC_000005.9:g.226094_226095insA
NC_000005.9:g.226095dup
NM_004168.2:c.554dupA

Protein change:

A138fs

Links:

dbSNP: rs1173940446

NCBI 1000 Genomes Browser:

rs1173940446

Molecular consequence:

NM_001294332.2:c.410dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001330758.2:c.554dup - frameshift variant - [Sequence Ontology: SO:0001589]
NM_004168.4:c.554dup - frameshift variant - [Sequence Ontology: SO:0001589]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002649952	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 28, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002649952

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 28, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Optimizing Genetic Workup in Pheochromocytoma and Paraganglioma by Integrating Diagnostic and Research Approaches.

Gieldon L, William D, Hackmann K, Jahn W, Jahn A, Wagner J, Rump A, Bechmann N, Nölting S, Knösel T, Gudziol V, Constantinescu G, Masjkur J, Beuschlein F, Timmers HJ, Canu L, Pacak K, Robledo M, Aust D, Schröck E, Eisenhofer G, Richter S, et al.

Cancers (Basel). 2019 Jun 11;11(6). doi:pii: E809. 10.3390/cancers11060809.

PubMed [citation]

PMID:: 31212687
PMCID:: PMC6627084

Details of each submission

From Ambry Genetics, SCV002649952.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The c.554dupA variant, located in coding exon 5 of the SDHA gene, results from a duplication of A at nucleotide position 554, causing a translational frameshift with a predicted alternate stop codon (p.A186Gfs*9). This alteration was identified in an individual with a personal history of a head/neck paraganglioma diagnosed under age 30 (Gieldon L et al. Cancers (Basel), 2019 Jun;11:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as "c.553_554insA (p.Ala186fs)" in published literature. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 7, 2024

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