ClinVar Miner

Submissions for variant NM_003000.2(SDHB):c.724C>A (p.Arg242Ser) (rs786203251)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226466 SCV000287789 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-05-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 242 of the SDHB protein (p.Arg242Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with paraganglioma (PMID: 19351833, Invitae). ClinVar contains an entry for this variant (Variation ID: 239443). This variant has been reported to affect SDHB protein function (PMID: 23175444). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg242 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19351833, 21173220, 22517554). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000492633 SCV000581213 pathogenic Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing The p.R242S pathogenic mutation (also known as c.724C>A), located in coding exon 7 of the SDHB gene, results from a C to A substitution at nucleotide position 724. The arginine at codon 242 is replaced by serine, an amino acid with dissimilar properties. This alteration was reported in 2/578 individuals with head and neck paragangliomas (Neumann HP et al. Cancer Res. 2009 Apr;69(8):3650-6). In addition, a different disease causing mutation, p.R242H, has been described at this position (Kim E et al. Endocr. Relat. Cancer 2015 Jun; 22(3):387-97). Functional studies using yeast models determined that the yeast-equivalent alteration of p.R242S, yR235S, results in an OXPHOS phenotype similar to the null strain; with no detectable SDH activity, 50% reduction in respiration, and increased genomic instability (Panizza E et al. Hum. Mol. Genet. 2013 Feb;22(4):804-15). 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 available evidence, this alteration is classified as a pathogenic mutation.
GeneDx RCV000523546 SCV000616875 pathogenic not provided 2017-05-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted SDHB c.724C>A at the cDNA level, p.Arg242Ser (R242S) at theprotein level, and results in the change of an Arginine to a Serine (CGC>AGC). This variant has been reported in atleast two individuals with head and neck paraganglioma (Neumann 2009). Functional assays in yeast demonstratedthat this variant affects SDH enzyme activity and increases mtDNA mutability and sensitivity to oxidative stress(Panizza 2013). SDHB Arg242Ser was not observed in large population cohorts (NHLBI Exome Sequencing Project,The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Serine differ in some properties, this isconsidered a semi-conservative amino acid substitution. SDHB Arg242Ser occurs at a position that is conservedacross species and is located in the second L(I)YR motif (Maio 2014, Saxena 2015). In silico analyses predict that thispathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, weconsider this variant to be pathogenic

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