chr1-17024040-C-T

Variant names:

• chr1-17024040-C-T
• rs397516835
• NM_003000.3:c.575G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_003000.3(SDHB):​c.575G>A​(p.Cys192Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. C192S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.08
• Publications: 5 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 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 29 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 chr1-17024040-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44645.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 1-17024040-C-T is Pathogenic according to our data. Variant chr1-17024040-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 142047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.575G>A	p.Cys192Tyr	missense_variant	Exon 6 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.521G>A	p.Cys174Tyr	missense_variant	Exon 6 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.575G>A	p.Cys192Tyr	missense_variant	Exon 6 of 8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary pheochromocytoma-paraganglioma Pathogenic:2

Feb 28, 2025

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.575G>A (p.Cys192Tyr) results in a non-conservative amino acid change in the encoded protein sequence. This variant affects a cysteine that has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Saxena_2016). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251156 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.575G>A has been reported in the literature in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome (example: Benn_2006, Burnichon_2009, Jochmanova_2017, Jochmanova_2020, Ding_2022, Tang_2024, Internal data). The following publications have been ascertained in the context of this evaluation (PMID: 16317055, 19454582, 35546442, 28374168, 32062700, 26719882, 34906457). ClinVar contains an entry for this variant (Variation ID: 142047). Based on the evidence outlined above, the variant was classified as pathogenic. -

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Section on Medical Neuroendocrinolgy, National Institutes of Health

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

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Pheochromocytoma/paraganglioma syndrome 4 Pathogenic:1

Nov 27, 2024

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16317055, 31492822, 28374168]. This variant is expected to disrupt protein structure [Myriad internal data]. -

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

Sep 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 192 of the SDHB protein (p.Cys192Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with SDHB-related conditions (PMID: 16317055, 19454582, 28374168, 34906457; internal data). ClinVar contains an entry for this variant (Variation ID: 142047). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SDHB protein function with a positive predictive value of 80%. This variant disrupts the p.Cys192 amino acid residue in SDHB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12000816, 17200167, 18382370, 22517554, 25371406, 27785149). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 31, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C192Y pathogenic mutation (also known as c.575G>A), located in coding exon 6 of the SDHB gene, results from a G to A substitution at nucleotide position 575. The cysteine at codon 192 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple individuals diagnosed with paraganglioma-pheochromocytoma (PGL-PCC) syndrome (Benn DE et al. J Clin Endocrinol Metab. 2006 Mar;91(3):827-36; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27; Jochmanova I et al. J. Cancer Res. Clin. Oncol. 2017 Aug;143:1421-1435). The cysteine at codon 192 has been shown to play a vital role coordinating the iron-sulfur cluster in SDHB protein (Iverson TM et al. J Biol Chem. 2012 Oct 12;287(42):35430-8). In addition, another alteration at codon 192 (p.C192R) has been reported in two individuals, one with a sporadic pheochromocytoma and the other with a paraganglioma (Neumann HP et al. N Engl J Med. 2002 May 9;3466(19):1459-66; Burnichon N et al. J Clin Endocrinol Metab. 2009 Aug;94(8):2817-27). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Pathogenic	4.2	H;.
PhyloP100		7.1
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-10	D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.97
MutPred		0.96		Loss of helix (P = 0.1706);.;
MVP		1.0
MPC		0.92
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.98
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs397516835; hg19: chr1-17350535; COSMIC: COSV64965920;