rs113560320

Variant names:

• chr11-61437820-G-A
• rs113560320
• NM_017841.4:c.232G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-61437820-G-A
• chr11-61437820-G-C

Variant summary

Our verdict is Pathogenic. The variant received 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in 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
• Publications: 30 publications found

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]

SDHAF2 Gene-Disease associations (from GenCC):

• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• pheochromocytoma/paraganglioma syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ENSG00000256591 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 821122.
• 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 VariationId is 401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHAF2	NM_017841.4	c.232G>A	p.Gly78Arg	missense_variant	Exon 2 of 4	ENST00000301761.7	NP_060311.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHAF2	ENST00000301761.7	c.232G>A	p.Gly78Arg	missense_variant	Exon 2 of 4	1	NM_017841.4	ENSP00000301761.3
ENSG00000256591	ENST00000541135.5	c.232G>A	p.Gly78Arg	missense_variant	Exon 2 of 5	4		ENSP00000443130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pheochromocytoma/paraganglioma syndrome 2 Pathogenic:2 Other:1

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 04, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 13, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 08, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 78 of the SDHAF2 protein (p.Gly78Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with paraganglioma (PMID: 20071235, 22241717, 28099933). It is commonly reported in individuals of Dutch ancestry (PMID: 6264239, 6286462, 19628817, 21224366, 21348866). ClinVar contains an entry for this variant (Variation ID: 401). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SDHAF2 function (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
DEOGEN2	Pathogenic	0.86	.;D;.;.;.
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
MutationAssessor	Pathogenic	4.1	.;H;.;.;.
PhyloP100		9.0
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
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs113560320; hg19: chr11-61205292;