Table 1.

Pathogenic and likely pathogenic variants in SDHx genes identified in this study

Gene	Nucleotide change	Predicted protein change	Mutation type	Germline status	S:F above cut-off	Phenotype	Reference SNP No	n patients (families)	AF in gnomAD in %	ClinVar	Known from literature/ Disease databases
SDHB	c.72+1G>T		splice	germline	yes	PGL	rs587782703	1	-	pathogenic	yes
	c.136C>T	p.(Arg46*)	stop	germline	yes	3x PGL	rs74315370	3	0.001805	pathogenic	yes
	c.166_170del	p.(Pro56Tyrfs*5)	fs	germline	yes	1x PGL	rs786202100	1	-	pathogenic	yes
	c.183T>G	p.(Tyr61*)	stop	somatic	yes	1x PGL	-	1	-	-	yes
	c.268C>T	p.(Arg90*)	stop	germline	yes	2x PGL, 1x HNP	rs74315366	3	0.00041	pathogenic	yes
	c.287–1G>C	-	splice	germline	yes	1x PGL	rs397516833	1	-	-	yes
	c.287–3G>C	-	potential splice	germline	yes	2x PGL	rs397516834	2	-	-	yes
	c.343C>T	p.(Arg115*)	stop	germline	yes	1x PGL	rs751000085	1	0.00081	pathogenic	yes
	c.348_352del	p.(Ile117Hisfs*5)	fs	germline	yes	1x PHEO	-	1	-	-	-
	c.423+1G>A	-	splice	germline	yes	3x PGL	rs398122805	3	0.0012	pathogenic	yes
	c.445_446del insGGTATCT	p.(Gln149Glyfs*11)	fs	germline	yes	1xPGL	-	1	-	-	yes
	c.503dup	p.(Gln169Alafs*10)	fs	germline	yes	2x PHEO	-	2(1)	-	-	-
	c.587G>A	p.(Cys196Tyr)	missense	germline	yes	1x PHEO	-	1	-	pathogenic	yes
	c.649C>T	p.(Arg217Cys)	missense	germline	no1	2x HNP	rs200245469	2	-	likely pathogenic	yes
	c.689G>A	p.(Arg230His)	missense	germline	yes	2x PGL	rs587782604	2	0.00041	pathogenic/ likely pathogenic	yes
	c.725G>A	p.(Arg242His)	missense	germline	yes	2x HNP, 1x PGL	rs74315368	3	0.00081	pathogenic	yes
SDHC	c.43C>T	p.(Arg15*)	stop	germline	yes	1x HNP	rs201286421	1	0.00082	pathogenic	yes
	c.126G>A	p.(Trp42*)	stop	germline	no	1x PGL	-	1	-	-	yes
SDHD	c.3G>T		startloss	somatic	yes	1xHNP	-	1	-	-	yes
	c.14G>A	p.(Trp5*)	stop	germline	yes	1x HNP	rs104894310	1	-	pathogenic	yes
	c.36_37del	p.(Ala13Profs*55)	fs	germline	yes	1xPHEO	-	1	-	-	yes
	c.49C>T	p.(Arg17*)	stop	germline	yes	1xHNP	-	1	-	-	yes
	c.53–2A>G		splice	germline	yes	1xHNP	-	1	-	-	-
	c.53dup	p.(Leu19Serfs*50)	fs	germline	yes	1xHNP	-	1	-	pathogenic/ likely pathogenic	-
	c.64C>T	p.(Arg22*)	stop	germline	yes	2xHNP	rs104894306	2(1)	-	pathogenic	yes
	c.169+1G>A		splice	germline	(yes)2	1x HNP	-	1	-	-	yes
	c.170–1G>T		splice	germline	yes	1x PHEO	-	1	0.00041	-	yes
	c.242C>T	p.(Pro81Leu)	missense	germline	yes (5/7)	7x HNP	rs80338844	7	0.0018	pathogenic	yes
	c.274G>T	p.(Asp92Tyr)	missense	germline	yes	2x HNP	rs80338845	2	-	pathogenic	yes
	c.284T>C	p.(Leu95Pro)	missense	germline	yes	1x PHEO, 1x PGL, 1x HNP	rs80338846	3(2)	-	pathogenic	yes
	c.298_301del	p.(Thr100Phefs*34)	fs	germline	yes	1x HNP	rs786203067	1	-	pathogenic	yes
	c.325C>T	p.(Gln109*)	stop	germline	yes	1x PHEO, 1x PGL	-	2(1)	-	pathogenic	yes
	c.337_340del	p.​(Asp113fs)	fs	somatic	yes	1x PGL	-	1	-	pathogenic	yes
	c.341A>G	p.(Tyr114Cys)	missense	germline	yes	2xHNP	rs104894304	2	-	pathogenic	yes
	c.416T>C	p.(Leu139Pro)	missense	germline	no	1xPHEO	rs80338847	1	-	pathogenic	yes
SDHA	c.1753C>T	p.(Arg585Trp)	missense	germline	yes	1xPHEO	rs200397144	1	0.0022	inconclusive	yes
SDHAF2	c.232G>A	p.(Gly78Arg)	missense	germline	yes	3xHNP	rs113560320	3(2)	-	pathogenic	yes

Abbreviations: AF, allele frequency; gnomAD, The Genome Aggregation Database; S:F, succinate:fumarate; SNP, single nucleotide polymorphism; n, number; fs, frameshift; PHEO, adrenal pheochromocytoma; PGL, extra-adrenal paraganglioma; HNP, head and neck paraganglioma

^1:Metabolic-Cluster 1 tumor despite normal S:F ration indicating aberrant SDH (likely normal tissue contamination)

^2:normal succinate:fumarate ratios were found in the first tumor tissue, but measurement of a second peace confirmed highly elevated succinate:fumarate ratios