1-17023973-C-G

Variant names:

• chr1-17023973-C-G
• rs1278834014
• NM_003000.3:c.642G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_003000.3(SDHB):​c.642G>C​(p.Gln214His) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000686 in 1,457,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q214R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SDHB NM_003000.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 7.04
• Publications: 6 publications found

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]

SDHB Gene-Disease associations (from GenCC):

• Carney-Stratakis syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• gastrointestinal stromal tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• pheochromocytoma/paraganglioma syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• mitochondrial complex 2 deficiency, nuclear type 4

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Cowden disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex II deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 35 uncertain in NM_003000.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-17023974-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 412493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 1-17023973-C-G is Pathogenic according to our data. Variant chr1-17023973-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 438426.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003000.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	NM_003000.3	MANE Select	c.642G>C	p.Gln214His	missense splice_region	Exon 6 of 8	NP_002991.2
	SDHB	NM_001407361.1		c.588G>C	p.Gln196His	missense splice_region	Exon 6 of 8	NP_001394290.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SDHB	ENST00000375499.8	TSL:1 MANE Select	c.642G>C	p.Gln214His	missense splice_region	Exon 6 of 8	ENSP00000364649.3
	SDHB	ENST00000714034.1		c.687G>C	p.Gln229His	missense splice_region	Exon 7 of 9	ENSP00000519325.1
	SDHB	ENST00000491274.6	TSL:5	c.600G>C	p.Gln200His	missense splice_region	Exon 6 of 8	ENSP00000480482.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457408 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725284

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108190

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:1 Uncertain:2

Dec 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SDHB c.642G>C (p.Gln214His) results in a non-conservative amino acid change located in the 4Fe-4S dicluster domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. As the variant alters the last conserved nucleotide of exon 6 adjacent to the intron 6 canonical splicing donor site, several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing due to retention of intron 6 and a loss of function outcome (Higashi_2022). The variant was absent in 251294 control chromosomes. c.642G>C has been reported in the literature and observed at our laboratory in individuals affected with features of Hereditary Paraganglioma-Pheochromocytoma Syndrome (example, Brouwers_2006, Timmers_2007, Sue_2015, Jochmanova_2017, Bayley_2020, Choi_2020, Yonamine_2022, Higashi_2022, internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 31492822, 16912137, 33397040, 35869040, 28374168, 25371406, 17200167, 34439168). ClinVar contains an entry for this variant (Variation ID: 438426). Based on the evidence outlined above, the variant was classified as pathogenic.

Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glutamine with histidine at codon 214 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). Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, protein and RNA functional studies have not been reported for this variant. This variant has been reported in individuals affected with pheochromocytoma/paraganglioma (PMID: 17200167, 28374168, 31492822, 33397040). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Pheochromocytoma;C0238198:Gastrointestinal stromal tumor;C1861848:Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

Nov 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 214 of the SDHB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SDHB protein. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with paraganglioma (PMID: 16912137, 28374168, 31492822, 33397040, 35869040; internal data). ClinVar contains an entry for this variant (Variation ID: 438426). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Gln214 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been observed in individuals with SDHB-related conditions (internal data), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.642G>C pathogenic mutation (also known as p.Q214H), located in coding exon 6 of the SDHB gene, results from a G to C substitution at nucleotide position 642. The amino acid change results in glutamine to histidine at codon 214, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant was reported in individuals with features consistent with SDHB-related paraganglioma-pheochromocytoma syndrome (Brouwers FM et al. J Clin Endocrinol Metab, 2006 Nov;91:4505-9; Jochmanova I et al. J Cancer Res Clin Oncol, 2017 Aug;143:1421-1435; Yonamine M et al. Cancers (Basel), 2021 Aug;13:; Higashi S et al. Hum Genome Var, 2022 Jul;9:25; Ha C et al. Front Genet, 2023 Oct;14:1283611). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species, and this amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a partial intron retention (Higashi S et al. Hum Genome Var, 2022 Jul;9:25; Ha C et al. Front Genet, 2023 Oct;14:1283611; Ambry internal data). Other variant(s) impacting the same donor site (c.641A>G and c.642+1G>C) have been shown to have a similar impact on splicing in individual(s) with features consistent with paraganglioma-pheochromocytoma syndrome (Ambry internal data). In addition, as a missense substitution p.Q214H is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Pheochromocytoma/paraganglioma syndrome 4 Uncertain:1

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.89). Different nucleotide change resulting in same amino acid change has been previously reported to be associated with SDHB related disorder (ClinVar ID: VCV000480788 / PMID: 33219105). However, the evidence of pathogenicity is insufficient at this time. A different missense change at the same codon (p.Gln214Arg) has been reported to be associated with SDHB related disorder (PMID: 24659481). Therefore, this variant is classified as Uncertain significance according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.024	D
Sift4G	Benign	0.12	T
Polyphen		0.95	P
Vest4		0.87
MutPred		0.54		Gain of catalytic residue at Q214 (P = 0.0229)
MVP		0.99
MPC		0.67
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.65
gMVP		0.94
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: 0

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

Other links and lift over

dbSNP: rs1278834014; hg19: chr1-17350468;