rs113560320

chr11-61437820-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_017841.4(SDHAF2):c.232G>A(p.Gly78Arg) 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. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G78E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHAF2 NM_017841.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 8.97

Genes affected

SDHAF2 (HGNC:26034): (succinate dehydrogenase complex assembly factor 2) This gene encodes a mitochondrial assembly factor needed for the flavination of a succinate dehydrogenase complex subunit (SDHA), which is required for activity of the succinate dehydrogenase complex. Mutations in this gene are associated with paraganglioma. [provided by RefSeq, May 2022]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-61437821-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 821122.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 11-61437820-G-A is Pathogenic according to our data. Variant chr11-61437820-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-61437820-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHAF2	NM_017841.4	c.232G>A	p.Gly78Arg	missense_variant	2/4	ENST00000301761.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHAF2	ENST00000301761.7	c.232G>A	p.Gly78Arg	missense_variant	2/4	1	NM_017841.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 2 Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 04, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2020

Founder pathogenic variant in the Dutch population (Hensen 2012); Published functional studies demonstrate a damaging effect: variant results in a destabilized SDHAF2 protein and impairs SDHAF2-SDHA interaction (Hao 2009, Bezawork-Gelata 2014); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20972721, 19628817, 6286462, 28099933, 30050099, 24414418, 27587393, 22904323, 26627475, 23062074, 20071235, 21348866, 21224366, 25720320, 20938758, 23154507, 21082267, 21547462, 28384794, 20304625, 24739310, 31212687) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 08, 2018

The p.G78R pathogenic mutation (also known as c.232G>A), located in coding exon 2 of the SDHAF2 gene, results from a G to A substitution at nucleotide position 232. The glycine at codon 78 is replaced by arginine, an amino acid with dissimilar properties. This mutation is considered a Dutch founder mutation and has been identified in multiple families with hereditary head and neck paragangliomas (HNPGL) (Hensen, EF et al. Clin Genet. 2012 Mar;81(3):284-8; Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Hoekstra AS et al. Oncotarget, 2017 Feb;8:14525-14536). In addition, this mutation co-segregated with disease in a Spanish family with HNPGL (Bayley, JP et al. Lancet Oncol. 2010 Apr;11(4):366-72) and was also observed in an apparently sporadic case of HNPGL in a patient with a right tympanic PGL (Piccini, V et al. Endocr Relat Cancer. 2012 Apr 10;19(2):149-55). Functional studies suggest that this mutation leads to a significant loss of flavination of SDHA, loss of activity of the succinate dehydrogenase complex, and reduced stability of SDHAF2 (Hao, HX et al. Science. 2009 Aug 28;325(5944):1139-42; Bezawork-Geleta A et al. FASEB J., 2014 Apr;28:1794-804). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Sep 20, 2020

This sequence change replaces glycine with arginine at codon 78 of the SDHAF2 protein (p.Gly78Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with paraganglioma in multiple families, and is considered a founder mutation in the Dutch population (PMID: 19628817, 21224366, 6286462, 6264239, 21348866). This variant was also observed in an individual with paraganglioma (PMID: 22241717) and a Spanish family, segregating with paraganglioma (PMID: 20071235). The studies have shown a parent-of-origin inheritance pattern (paternal transmission) in these families (PMID: 19628817, 21224366, 20071235, 28099933), but the clinical significance of this is not established yet. ClinVar contains an entry for this variant (Variation ID: 401). Experimental studies have shown that this missense change impairs interaction with SDHA, reduces protein stability, and decreases SDHA flavination (PMID: 19628817, 24414418). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.7	D;D;.;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.99, 0.99, 0.98, 0.99
MutPred		0.95		Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);Gain of MoRF binding (P = 0.0157);
MVP		0.91
MPC		0.79
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.98
gMVP		0.86

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: rs113560320; hg19: chr11-61205292;