ClinVar Miner

Submissions for variant NM_003000.3(SDHB):c.689G>A (p.Arg230His) (rs587782604)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131970 SCV000187028 pathogenic Hereditary cancer-predisposing syndrome 2018-02-12 criteria provided, single submitter clinical testing The p.R230H pathogenic mutation (also known as c.689G>A), located in coding exon 7 of the SDHB gene, results from a G to A substitution at nucleotide position 689. The arginine at codon 230 is replaced by histidine, an amino acid with highly similar properties. In one study, this mutation was detected in a Mexican kindred in two relatives with head and neck paragangliomas whose tumors demonstrated loss of SDHB protein on immunohistochemistry (Cerecer-Gil et al. Clin Cancer Res 2010 Aug 15; 16(16):4148-54). An individual diagnosed with an autosomal recessive mitochondrial disease and leukoencephalopathy was found to be a compound heterozygote for SDHB p.D48V (c.143A>T) and SDHB p.R230H (c.689G>A) (Grønborg S et al. JIMD Rep. 2017 Sep;33:69-77). Furthermore, p.R230H has been reported in numerous additional kindreds with hereditary paraganglioma-pheochromocytoma, sporadic paraganglioma-pheochromocytoma, and familial renal cell carcinoma (Amar et al. J Clin Oncol. 2005 Dec1; 23(34):8812-8; Said-Al-Naief et al. Head Neck Pathol. 2008 Dec;2(4): 272-8; Ricketts CJ et al. J Urol. 2012; 188:2063-71; Cascón A et al. J Clin Endocrinol Metab. 2009; 94:1701-5; Burnichon N et al. J Clin Endocrinol Metab. 2009; 94:2817-27). Two other pathogenic mutations (p.R230C and p.R230L) have also been described at this same codon. Based on available evidence, p.R230H is classified as a pathogenic mutation.
GeneDx RCV000183215 SCV000235635 pathogenic not provided 2021-11-19 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 16314641, 24102379, 20592014, 20208144, 20614293, 23083876, 19454582, 18551016, 25695889, 19393419, 19258401, 16912137, 19576851, 24092654, 24509376, 17200167, 19351833, 26259135, 28374168, 29386252, 30045248, 29909963, 30050099, 30997073, 31365623, 30155846, 32581362, 32859697, 27604842, 27539324, 31666924, 30877234, 32741965, 32561571, 30787465, 31492822)
Invitae RCV000456660 SCV000554030 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2020-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 230 of the SDHB protein (p.Arg230His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in multiple individuals affected with pheochromocytomas, paragangliomas and renal cell carcinomas (PMID: 17200167, 20614293, 23083876, 24509376, 25695889, 26259135, 27539324), and was shown to segregate with disease in two families (PMID: 20592014 and Invitae database). ClinVar contains an entry for this variant (Variation ID: 142637). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Two additional missense substitutions at this codon (p.Arg230Cys, p.Arg230Leu) have been determined to be pathogenic (PMID: 14500403, 16314641, 18382370, 19351833, 27539324, 24939699, Invitae database). This suggests that the arginine residue is critical for SDHB protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000660259 SCV000782280 pathogenic Paragangliomas 4 2016-11-01 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762865 SCV000893245 pathogenic Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma 2018-10-31 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000131970 SCV000992188 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Section on Medical Neuroendocrinolgy,National Institutes of Health RCV000505312 SCV000599524 pathogenic Hereditary Paraganglioma-Pheochromocytoma Syndromes no assertion criteria provided research
OMIM RCV001310280 SCV001500013 pathogenic Mitochondrial complex 2 deficiency, nuclear type 4 2010-08-15 no assertion criteria provided literature only
OMIM RCV000660259 SCV001502664 pathogenic Paragangliomas 4 2010-08-15 no assertion criteria provided literature only

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