NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp) AND Paragangliomas 5

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 24, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000148027.10

Allele description [Variation Report for NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)]

NM_004168.4(SDHA):c.1753C>T (p.Arg585Trp)

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.1753C>T (p.Arg585Trp)

HGVS:

NC_000005.10:g.251427C>T
NG_012339.1:g.38187C>T
NM_001294332.2:c.1609C>T
NM_001330758.2:c.1552-2966C>T
NM_004168.4:c.1753C>TMANE SELECT
NP_001281261.1:p.Arg537Trp
NP_004159.2:p.Arg585Trp
LRG_315t1:c.1753C>T
LRG_315:g.38187C>T
LRG_315p1:p.Arg585Trp
NC_000005.9:g.251542C>T
NM_004168.2:c.1753C>T
NM_004168.3:c.1753C>T
p.R585W

Protein change:

R537W; ARG585TRP

Links:

OMIM: 600857.0009; dbSNP: rs200397144

NCBI 1000 Genomes Browser:

rs200397144

Molecular consequence:

NM_001330758.2:c.1552-2966C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001294332.2:c.1609C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004168.4:c.1753C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000246127	OMIM	no assertion criteria provided	Pathogenic (Sep 1, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000785685	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 1, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 27011036, 21752896, 23666964 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004045372	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Apr 24, 2023)	unknown	clinical testing	PubMed (4) [See all records that cite these PMIDs] 30050099, 28546994, 21752896, 23666964 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000246127

OMIM

no assertion criteria provided

Pathogenic
(Sep 1, 2011)

germline

literature only

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

SCV000785685

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 1, 2017)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV004045372

Myriad Genetics, Inc.

criteria provided, single submitter

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

Likely pathogenic
(Apr 24, 2023)

unknown

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic.

Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, Trent JC, von Mehren M, Wright JA, Schiffman JD, Raygada M, Pacak K, Meltzer PS, Miettinen MM, Stratakis C, Janeway KA, Helman LJ.

JAMA Oncol. 2016 Jul 1;2(7):922-8. doi: 10.1001/jamaoncol.2016.0256.

PubMed [citation]

PMID:: 27011036
PMCID:: PMC5472100

Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma.

Richter S, Gieldon L, Pang Y, Peitzsch M, Huynh T, Leton R, Viana B, Ercolino T, Mangelis A, Rapizzi E, Menschikowski M, Aust D, Kroiss M, Beuschlein F, Gudziol V, Timmers HJ, Lenders J, Mannelli M, Cascon A, Pacak K, Robledo M, Eisenhofer G, et al.

Genet Med. 2019 Mar;21(3):705-717. doi: 10.1038/s41436-018-0106-5. Epub 2018 Jul 27.

PubMed [citation]

PMID:: 30050099
PMCID:: PMC6353556

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000246127.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In a French patient with paragangliomas (PGL5; 614165), Korpershoek et al. (2011) identified a heterozygous germline c.1753C-T transition (c.1753C-T, NM_004168) in the SDHA gene, resulting in an arg585-to-trp (R585W) substitution. The mutation was found in 1 (0.1%) of 972 Dutch controls. Tumor tissue showed loss of heterozygosity for SDHA and lack of SDHA and SDHB (185470) immunostaining.

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

From Counsyl, SCV000785685.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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., SCV004045372.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30050099, 28546994, 21752896, 23666964]. This variant is expected to disrupt protein structure [Myriad internal data].

#	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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