NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 2, 2022
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:: RCV001810833.14

Allele description [Variation Report for NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)]

NM_003002.4(SDHD):c.341A>G (p.Tyr114Cys)

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.341A>G (p.Tyr114Cys)

HGVS:

NC_000011.10:g.112094831A>G
NG_012337.3:g.12985A>G
NM_001276503.2:c.196A>G
NM_001276504.2:c.224A>G
NM_001276506.2:c.*39A>G
NM_003002.4:c.341A>GMANE SELECT
NP_001263432.1:p.Met66Val
NP_001263433.1:p.Tyr75Cys
NP_002993.1:p.Tyr114Cys
LRG_9t1:c.341A>G
LRG_9:g.12985A>G
LRG_9p1:p.Tyr114Cys
NC_000011.9:g.111965555A>G
NM_003002.2:c.341A>G
NM_003002.3:c.341A>G
NR_077060.2:n.430A>G
O14521:p.Tyr114Cys

Protein change:

M66V; TYR114CYS

Links:

UniProtKB: O14521#VAR_017872; OMIM: 602690.0007; dbSNP: rs104894304

NCBI 1000 Genomes Browser:

rs104894304

Molecular consequence:

NM_001276506.2:c.*39A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001276503.2:c.196A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001276504.2:c.224A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_003002.4:c.341A>G - missense variant - [Sequence Ontology: SO:0001583]
NR_077060.2:n.430A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001477811	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Jul 26, 2019)	germline	clinical testing	Citation Link,
SCV002599968	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Nov 2, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001477811

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Jul 26, 2019)

germline

clinical testing

Citation Link,

SCV002599968

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Nov 2, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Details of each submission

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001477811.1

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

Description

The SDHD c.341A>G; p.Tyr114Cys variant (rs104894304) is reported in the literature in multiple individuals and families affected with pheochromocytoma or paraganglioma (Andrews 2018, Antonello 2008, Benn 2006, Braun 2005, Fish 2007, Milunsky 2001, Neumann 2004, Piccini 2012, Richter 2019), and is a common variant in Italy due to a founder effect (Schiavi 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 6900), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 114 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses in yeast demonstrate a complete loss of ubiquinone reductase activity (Panizza 2013). Based on available information, this variant is considered to be pathogenic. References: Andrews KA et al. Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018 Jun;55(6):384-394. Antonello M et al. Role of the genetic study in the management of carotid body tumor in paraganglioma syndrome. Eur J Vasc Endovasc Surg. 2008 Nov;36(5):517-9. Benn DE et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Braun S et al. Active succinate dehydrogenase (SDH) and lack of SDHD mutations in sporadic paragangliomas. Anticancer Res. 2005 Jul-Aug;25(4):2809-14. Fish JH et al. Systematic screening and treatment evaluation of hereditary neck paragangliomas. Head Neck. 2007 Sep;29(9):864-73. Milunsky JM et al. Novel mutations and the emergence of a common mutation in the SDHD gene causing familial paraganglioma. Am J Med Genet. 2001 May 15;100(4):311-4. Neumann HP et al. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. JAMA. 2004 Aug 25;292(8):943-51. Panizza E et al. Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. Hum Mol Genet. 2013 Feb 15;22(4):804-15. Piccini V et al. Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55. Richter S et al. Metabolome-guided genomics to identify pathogenic variants in isocitrate dehydrogenase, fumarate hydratase, and succinate dehydrogenase genes in pheochromocytoma and paraganglioma. Genet Med. 2019 Mar;21(3):705-717. Schiavi F et al. The endemic paraganglioma syndrome type 1: origin, spread, and clinical expression. J Clin Endocrinol Metab. 2012 Apr;97(4):E637-41.

#	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

From GeneDx, SCV002599968.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: protein instability, reduced SDH enzyme activity, and increased mtDNA mutability and sensitivity to oxidative stress (Panizza et al., 2013; Chang et al., 2015); This variant is associated with the following publications: (PMID: 17208193, 26916530, 19454582, 30050099, 34906457, 23175444, 22456618, 16080530, 15066320, 21792967, 18826997, 26259135, 26549015, 15883710, 15988378, 25394176, 22241717, 18692411, 16317055, 21844248, 27279923, 16080474, 15328326, 11343322, 9295078, 29386252, 23433498, 17102086, 25275255, 30375904, 34939938, 17563904, 25328978)

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

Last Updated: Apr 20, 2024

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