rs786201095

Positions:

• chr1-17028643-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The ENST00000375499.8(SDHB):​c.380T>G​(p.Ile127Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I127L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: SDHB ENST00000375499.8 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 8.56

Genes affected

SDHB (HGNC:10681): (succinate dehydrogenase complex iron sulfur subunit B) This tumor suppressor gene encodes the iron-sulfur protein subunit of the succinate dehydrogenase (SDH) enzyme complex which plays a critical role in mitochondria. The SDH enzyme complex is composed of four nuclear-encoded subunits. This enzyme complex converts succinate to fumarate which releases electrons as part of the citric acid cycle, and the enzyme complex additionally provides an attachment site for released electrons to be transferred to the oxidative phosphorylation pathway. The SDH enzyme complex plays a role in oxygen-related gene regulation through its conversion of succinate, which is an oxygen sensor that stabilizes the hypoxia-inducible factor 1 (HIF1) transcription factor. Sporadic and familial mutations in this gene result in paragangliomas, pheochromocytoma, and gastrointestinal stromal tumors, supporting a link between mitochondrial dysfunction and tumorigenesis. Mutations in this gene are also implicated in nuclear type 4 mitochondrial complex II deficiency. [provided by RefSeq, Jun 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in ENST00000375499.8
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 1-17028643-A-C is Pathogenic according to our data. Variant chr1-17028643-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-17028643-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3	c.380T>G	p.Ile127Ser	missense_variant	4/8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.369+11T>G		intron_variant			NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.380T>G	p.Ile127Ser	missense_variant	4/8	1	NM_003000.3	ENSP00000364649	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251458 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000752 AC: 11 AN: 1461860 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Paragangliomas 4 Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 23, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 08, 2023	This missense variant replaces isoleucine with serine at codon 127 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies do not support pathogenicity, but may not be measuring the deficiency associated with this ferredoxin domain variant (PMID: 15987702, 25972245, 28070496, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 15987702, 16317055, 16912137,16916404,17200167, 17667967,19001511,19802898, 21820839, 23282968, 25371406, 25683602, 28374168, 29386252). The variant has also been observed to segregate or occur in a familial context in several of these families (PMID: 16916404, 16317055, 25683602, 28374168, 29386252). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2024	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16916404, 30050099, 24623741, 31308404, 29386252, 30201732]. This variant is expected to disrupt protein structure [Myriad internal data]. -

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 10, 2018	The SDHB c.380T>G; p.Ile127Ser variant (rs786201095) has been observed in multiple individuals with a personal history of pheochromocytoma, paraganglioma, and/or gastrointestinal stromal tumor (Benn 2006, Bolland 2006, Brouwers 2006, Collins 2012, Miettinen 2013). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 183814) and observed in the European (Non-Finnish) population at a low overall frequency of 0.0027% (3/111678 alleles) in the Genome Aggregation Database. The isoleucine at codon 127 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Functional studies demonstrate that this variant exhibits enzymatic activity and mitochondrial SDH assembly similar to wild-type (Kim 2015), however levels of succinate were elevated in the tumors of individuals with this variant (Pollard 2005). Based on available information, this variant is considered likely pathogenic. References: Benn D et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36. Bolland M et al. Gastrointestinal stromal tumour in succinate dehydrogenase subunit B mutation-associated familial phaeochromocytoma/paraganglioma. ANZ J Surg. 2006 Aug;76(8):763-4. Brouwers F et al. High frequency of SDHB germline mutations in patients with malignant catecholamine-producing paragangliomas: implications for genetic testing. J Clin Endocrinol Metab. 2006 Nov;91(11):4505-9. Collins N et al. Contiguous bilateral head and neck paragangliomas in a carrier of the SDHB germline mutation. J Vasc Surg. 2012 Jan;55(1):216-9. Kim E et al. Structural and functional consequences of succinate dehydrogenase subunit B mutations. Endocr Relat Cancer. 2015 Jun;22(3):387-97. Miettinen M et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013 Feb;37(2):234-40. Pollard P et al. Accumulation of Krebs cycle intermediates and over-expression of HIF1alpha in tumours which result from germline FH and SDH mutations. Hum Mol Genet. 2005 Aug 1;14(15):2231-9. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2024	Published functional studies are inconclusive: enzymatic activity and mitochondrial SDH assembly similar to wild-type; elevated levels of succinate or loss of SDHB on immunohistochemistry suggesting an alternate method of pathogenicity (PMID: 25972245, 28070496, 15987702); 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: 26916530, 19215943, 25394176, 15987702, 17667967, 24886695, 25972245, 21820839, 16912137, 19802898, 17200167, 25014000, 25683602, 16317055, 16916404, 25371406, 19001511, 28070496, 28738844, 28374168, 29386252, 28973655, 23083876, 28152038, 30728895, 30303539, 23282968, 30050099, 31447099, 30787465, 32741965, 33087929, 34906457, 32782288, 34308366, 35668420) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2018	- -

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2017	Variant summary: The SDHB c.380T>G (p.Ile127Ser) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was absent in ExAC but was found in 3/246418 control chromosomes. This variant has been reported in multiple affected families/patients with variable phenotype including paragangliomas and GIST with evidence of co-segregation of the variant with disease (Pollad_2005, Benn_2006, Brouwers_2006, Joshua_2009, Thrimmers_2007 and Bolland_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Functional studies show activity comparable to WT level (Kim_SDHB_ERC_2015). This functional evidence is outweighted by strong clinical data which support a causative role of this variant. Taken together, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 29, 2024	This missense variant replaces isoleucine with serine at codon 127 of the SDHB protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies do not support pathogenicity, but may not be measuring the deficiency associated with this ferredoxin domain variant (PMID: 15987702, 25972245, 28070496, 28738844). This variant has been reported in numerous individuals affected with paraganglioma and pheochromocytoma in the literature (PMID: 15987702, 16317055, 16912137,16916404,17200167, 17667967,19001511,19802898, 21820839, 23282968, 25371406, 25683602, 28374168, 29386252). The variant has also been observed to segregate or occur in a familial context in several of these families (PMID: 16916404, 16317055, 25683602, 28374168, 29386252). This variant has been identified in 3/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Carney triad Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Section on Endocrinology and Genetics, National Institutes of Health / The Eunice Kennedy Shriver National Institute of Child Health and Human Development

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Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Paragangliomas 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 127 of the SDHB protein (p.Ile127Ser). This variant is present in population databases (rs786201095, gnomAD 0.003%). This missense change has been observed in individuals with paraganglioma, metastatic paraganglioma, pheochromocytoma, and gastrointestinal stromal tumor (PMID: 15987702, 16317055, 16912137, 16916404, 17200167, 19001511, 19215943, 19802898, 21820839, 23282968, 25683602). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 183814). 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%. Experimental studies have shown that this missense change does not substantially affect SDHB function (PMID: 25972245). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -

Gastrointestinal stromal tumor;C1708353:Hereditary pheochromocytoma-paraganglioma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 13, 2018

The p.Ile127Ser variant in SDHB has been reported in over 40 individuals with pa ragangliomas, pheochromocytomas, or gastrointestinal stromal tumors (GISTs) and segregated with disease in at least 7 relatives in these families (Bolland 2006, Benn 2006, Timmers 2007, Miettinen 2013, Martucci 2015, Sue 2015, Boikos 2016, Jochmanova 2017, Andrews 2018). This variant has also been reported in ClinVar ( Variation ID# 183814). In addition, three other variants at this position (p.Ile 127Asn, p.Ile127Leu, p.Ile127Thr) have been reported in the HGMD database in ind ividuals with paraganglioma, pheochromocytoma, and renal cell carcinoma (Stenson 2017). In vitro functional studies provide some evidence that the p.Ile127Ser v ariant may not impact protein function (Kim 2015). However, these types of assay s may not accurately represent biological function. This variant has been identi fied in 3/111678 European chromosomes by the Genome Aggregation Database (gnomAD , http://gnomad.broadinstitute.org). Please note that for diseases with clinical variability or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and conserva tion analysis suggest that the p.Ile127Ser variant may impact the protein, thoug h this information is not predictive enough to determine pathogenicity. In summa ry, this variant meets criteria to be classified as pathogenic for hereditary pa raganglioma/pheochromocytoma and GIST in an autosomal dominant manner based upon its presence in affected individuals, segregation studies, and low frequency in controls. ACMG/AMP Criteria applied: PS4, PP1_Strong, PM2, PP3. -

Gastrointestinal stromal tumor Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 31, 2023

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Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2022

The p.I127S pathogenic mutation (also known as c.380T>G), located in coding exon 4 of the SDHB gene, results from a T to G substitution at nucleotide position 380. The isoleucine at codon 127 is replaced by serine, an amino acid with dissimilar properties. This mutation is located in the iron-sulphur cluster binding domain of SDHB. One study detected this mutation in the germline of an individual with a history of paraganglioma. DNA analysis of the paraganglioma tumor identified a deletion of 1p encompassing the SDHB locus (Pollard PJ et al. Hum. Mol. Genet. 2005 Aug;14:2231-9). This alteration has been reported in numerous individuals with paraganglioma, pheochromocytoma, and/or gastrointestinal stromal tumor (GIST) (Benn DE et al. J. Clin. Endocrinol. Metab. 2006 Mar;91:827-36; Brouwers FM et al. J. Clin. Endocrinol. Metab. 2006 Nov;91:4505-9; Collins N and Dietzek A J. Vasc. Surg. 2012 Jan;55:216-9; Miettinen M et al. Am. J. Surg. Pathol. 2013 Feb;37:234-40; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435; Andrews KA et al. J. Med. Genet. 2018 Jun;55(6):384-394). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.3	H;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.6	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.99
MutPred		0.93		Gain of disorder (P = 0.0019);.;.;
MVP		1.0
MPC		0.84
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786201095; hg19: chr1-17355138;