NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter) AND Paragangliomas 5

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 21, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000411416.11

Allele description [Variation Report for NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter)]

NM_004168.4(SDHA):c.1534C>T (p.Arg512Ter)

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.1534C>T (p.Arg512Ter)

Other names:

p.Arg512*

HGVS:

NC_000005.10:g.240459C>T
NG_012339.1:g.27219C>T
NM_001294332.2:c.1390C>T
NM_001330758.2:c.1534C>T
NM_004168.4:c.1534C>TMANE SELECT
NP_001281261.1:p.Arg464Ter
NP_001317687.1:p.Arg512Ter
NP_004159.2:p.Arg512Ter
LRG_315t1:c.1534C>T
LRG_315:g.27219C>T
LRG_315p1:p.Arg512Ter
NC_000005.9:g.240574C>T
NM_004168.2:c.1534C>T
NM_004168.3:c.1534C>T

Protein change:

R464*

Links:

dbSNP: rs748089700

NCBI 1000 Genomes Browser:

rs748089700

Molecular consequence:

NM_001294332.2:c.1390C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330758.2:c.1534C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004168.4:c.1534C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Paragangliomas 5 (PPGL5)
Synonyms:: PHEOCHROMOCYTOMA/PARAGANGLIOMA SYNDROME 5
Identifiers:: MONDO: MONDO:0013602; MedGen: C3279992; Orphanet: 29072; OMIM: 614165

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488005	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Dec 13, 2015)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001786670	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020)	Pathogenic (Mar 11, 2021)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22955521, 25720320 Citation Link,
SCV004018616	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 21, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000488005

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely pathogenic
(Dec 13, 2015)

unknown

clinical testing

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

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV001786670

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)

Pathogenic
(Mar 11, 2021)

unknown

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV004018616

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Apr 21, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors.

Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL.

Mod Pathol. 2013 Feb;26(2):289-94. doi: 10.1038/modpathol.2012.153. Epub 2012 Sep 7.

PubMed [citation]

PMID:: 22955521

SDHB/SDHA immunohistochemistry in pheochromocytomas and paragangliomas: a multicenter interobserver variation analysis using virtual microscopy: a Multinational Study of the European Network for the Study of Adrenal Tumors (ENS@T).

Papathomas TG, Oudijk L, Persu A, Gill AJ, van Nederveen F, Tischler AS, Tissier F, Volante M, Matias-Guiu X, Smid M, Favier J, Rapizzi E, Libe R, Currás-Freixes M, Aydin S, Huynh T, Lichtenauer U, van Berkel A, Canu L, Domingues R, Clifton-Bligh RJ, Bialas M, et al.

Mod Pathol. 2015 Jun;28(6):807-21. doi: 10.1038/modpathol.2015.41. Epub 2015 Feb 27.

PubMed [citation]

PMID:: 25720320

Details of each submission

From Counsyl, SCV000488005.2

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

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

From Illumina Laboratory Services, Illumina, SCV001786670.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The SDHA c.1534C>T (p.Arg512Ter) variant is a stop-gained variant that is predicted to result in a premature termination or absence of the protein. The p.Arg512Ter variant has been reported in two studies in which it was identified as a germline variant in at least two affected individuals including one individual with a paraganglioma and one individual with a gastrointestinal stromal tumor (Wagner et al. 2013; Papathomas et al. 2015). The p.Arg512Ter variant is reported at a frequency of 0.000078 in the European (non-Finnish) population from of the Genome Aggregation Database. This allele frequency is high but is may be consistent with reduced penetrance. Based on the available evidence and application of the ACMG criteria, the p.Arg512Ter variant is classified as pathogenic for hereditary pheochromocytoma-paraganglioma syndrome.

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

From Myriad Genetics, Inc., SCV004018616.1

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

Description

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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

Last Updated: Oct 8, 2024

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