rs104894304

Positions:

• chr11-112094831-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_003002.4(SDHD):​c.341A>G​(p.Tyr114Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y114H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHD NM_003002.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.93

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_003002.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-112094830-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 993407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 11-112094831-A-G is Pathogenic according to our data. Variant chr11-112094831-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 6900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-112094831-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4	c.341A>G	p.Tyr114Cys	missense_variant	4/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8	c.341A>G	p.Tyr114Cys	missense_variant	4/4	1	NM_003002.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:3

Pathogenic, no assertion criteria provided	research	Section on Medical Neuroendocrinolgy, National Institutes of Health	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2013	The Tyr114Cys variant in SDHD was originally reported in one German individual w ith familial paraganglioma (Milunsky, 2001) and subsequently reported in one Aus trian individual with hereditary neck paraganglioma (HNPGL) where the variant se gregated with disease in 7 affected relatives from the same family (Fish, 2007). Recently, the Tyr114Cys variant has been reported to have arisen as a founder effect in a population originating from the region surrounding Torentino, Italy (Schiavi, 2012). Schiavi and colleagues studied 15 Italian index cases with HNPG L and found the Tyr114Cys variant segregated with disease in 138 affected relati ves from 95 families (Schiavi, 2012). Functional studies have shown that the Tyr 114Cys variant impacts protein function, and results in complete loss of ubiquin one reductase activity in yeast (Panizza, 2013). However, this in vitro assay ma y not accurately represent biological function. This variant has not been identi fied in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Tyr1 14Cys variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria t o be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segrega tion studies, absence from controls and functional evidence supporting the varia nt causing a functional defect on the protein. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces tyrosine with cysteine at codon 114 of the SDHD protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies in yeast have shown a complete loss of ubiquinone reductase activity, reduced protein expression, reduced superoxide generation (PMID: 17208193, 23175444, 25328978). This variant has been reported in numerous individuals affected with paragaglioma (PMID: 11343322, 16080474, 16317055, 17563904, 18692411, 22241717, 23433498, 27279923, 29386252, 30375904). The variant is a highly recurrent mutation in individuals native to Trentino, Italy (PMID: 22456618). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 02, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 26, 2019	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. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 10, 2021	The c.341A>G (p.Y114C) alteration is located in exon 4 (coding exon 4) of the SDHD gene. This alteration results from an A to G substitution at nucleotide position 341, causing the tyrosine (Y) at amino acid position 114 to be replaced by a cysteine (C). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in multiple individuals affected with paragangliomas (PGL) and/or pheochromocytomas (Neumann, 2004; Liapis, 2005; Benn, 2006; Antonello, 2008; Piccini, 2012; Zdrojowy-Wena, 2014; Bennedbæk, 2016; Richter, 2019). In addition, this alteration showed strong segregation with disease among 38 screened members of a family affected with head and neck PGL (Fish, 2007). Another study indicated that the p.Y114C alteration in the SDHD gene is an Italian founder mutation after finding this alteration in 287 out of 540 individuals from 95 kindred who were diagnosed with head and neck PGL (Schiavi, 2012). This amino acid position is highly conserved in available vertebrate species. Yeast complementation assays demonstrated that yeast cells transformed with this p.Y114C missense change are unable to grow on oxidative carbon sources and show increased mitochondrial DNA mutability (Panizza, 2013). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. ClinVar contains an entry for this variant (Variation ID: 6900). This missense change has been observed in individuals with pheochromocytomas and paragangliomas (PMID: 11343322, 16080474, 16317055, 17563904, 22456618, 23433498, 25275255, 27279923, 29386252). It is commonly reported in individuals of Trentino Italian ancestry (PMID: 22456618). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 114 of the SDHD protein (p.Tyr114Cys). Experimental studies have shown that this missense change affects SDHD function (PMID: 23175444). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Benign	0.95
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.40	T;T
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	0.045	A;A;A;A;A
PROVEAN	Benign	0.25	N;N
REVEL	Uncertain	0.61
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.46	T;T
Vest4		0.77
MutPred		0.57		Gain of catalytic residue at M112 (P = 0.0013);.;
MVP		0.97
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894304; hg19: chr11-111965555;