Submissions for variant NM_017841.4(SDHAF2):c.28del (p.Ser10fs)

dbSNP: rs1861838658

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001993356	SCV002232428	pathogenic	Hereditary pheochromocytoma-paraganglioma	2022-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1451844). This variant has not been reported in the literature in individuals affected with SDHAF2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser10Argfs*3) in the SDHAF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SDHAF2 are known to be pathogenic (PMID: 22241717, 26096992).
Ambry Genetics	RCV003303494	SCV003996854	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	The c.28delT variant, located in coding exon 1 of the SDHAF2 gene, results from a deletion of one nucleotide at nucleotide position 28, causing a translational frameshift with a predicted alternate stop codon (p.S10Rfs*3). The predicted stop codon occurs in the 5’ end of theSDHAF2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV003495260	SCV004362262	likely pathogenic	Paragangliomas 2	2023-06-30	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 1 of the SDHAF2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product by either nonsense mediated decay or by disrupting the signal presequence required for import into mitochondria. Translation of the frameshift extension is expected to bypass the in-frame methionine at codon 13 making re-initiation from this initiator codon unlikely, and re-initiation further downstream at the methionine at codon 47 would create a protein without the mitochondrial import signal. To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. 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 Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV001993356	SCV004825153	likely pathogenic	Hereditary pheochromocytoma-paraganglioma	2023-08-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 1 of the SDHAF2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product by either nonsense mediated decay or by disrupting the signal presequence required for import into mitochondria. Translation of the frameshift extension is expected to bypass the in-frame methionine at codon 13 making re-initiation from this initiator codon unlikely, and re-initiation further downstream at the methionine at codon 47 would create a protein without the mitochondrial import signal. To our knowledge, this variant has not been reported in individuals affected with SDHAF2-related disorders in the literature. 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 Likely Pathogenic.