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

gnomAD frequency: 0.00001  dbSNP: rs587782604

Total submissions: 15

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