ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs587782604
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Total submissions: 15
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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 2021-03-17 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; Ma X et al. Front Endocrinol (Lausanne) 2020 Dec;11:574662). 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 2023-03-29 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 (gnomAD); This variant is associated with the following publications: (PMID: 16314641, 24102379, 34906457, 34466344, 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, 34750850)
Invitae RCV000456660 SCV000554030 pathogenic Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 230 of the SDHB protein (p.Arg230His). This variant is present in population databases (rs587782604, gnomAD 0.0009%). This missense change has been observed in individuals with pheochromocytomas, paragangliomas and renal cell carcinomas (PMID: 17200167, 20614293, 23083876, 24509376, 25695889, 26259135, 27539324; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142637). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Arg230 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14500403, 16314641, 18382370, 19351833, 24939699, 27539324; Invitae). 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.
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.
CeGaT Center for Human Genetics Tuebingen RCV000183215 SCV002543875 pathogenic not provided 2022-04-01 criteria provided, single submitter clinical testing SDHB: PS4, PM2, PM5, PP1, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000505312 SCV002572270 pathogenic Hereditary pheochromocytoma-paraganglioma 2022-08-23 criteria provided, single submitter clinical testing Variant summary: SDHB c.689G>A (p.Arg230His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251416 control chromosomes. c.689G>A continues to be widely reported in the literature in multiple individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Amar_2005, Brouwers_2006, Amar_2007, Trimmers_2007, Meyer-Rochow_2009, Persu_2008). These data indicate that the variant is very likely to be associated with disease. No experimental evidence demonstrating an impact on protein function has been ascertained. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003474782 SCV004203033 pathogenic Gastrointestinal stromal tumor 2022-10-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000183215 SCV004224637 likely pathogenic not provided 2023-01-24 criteria provided, single submitter clinical testing PP3, PP4, PM2, PS4_moderate
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000183215 SCV004243193 likely pathogenic not provided 2024-02-06 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000660259 SCV004933633 likely pathogenic Paragangliomas 4 2024-02-08 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 23083876, 30050099, 20592014, 19576851]. This variant is expected to disrupt protein structure [Myriad internal data].
Section on Medical Neuroendocrinolgy, National Institutes of Health RCV000505312 SCV000599524 pathogenic Hereditary pheochromocytoma-paraganglioma 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 SCV004045983 pathogenic Paragangliomas 4 2010-08-15 no assertion criteria provided literature only

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