NM_003000.3:c.137_138delGAinsTG

Variant names:

• chr1-17044823-TC-CA
• NM_003000.3:c.137_138delGAinsTG
• SDHB p.Arg46Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_003000.3(SDHB):c.137_138delGAinsTG (p.Arg46Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R46G: Pathogenic (ClinVar VariationId 12785, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R46?: Uncertain_significance (ClinVar VariationId 591278, 0 stars); p.R46P: Uncertain_significance (ClinVar VariationId 3756934, 1 star); p.R46= (synonymous): Likely_benign (ClinVar VariationId 1100244, 1 star); p.R46= (synonymous): Benign/Likely_benign (ClinVar VariationId 646758, 2 stars); p.R46= (synonymous): Likely_benign (ClinVar VariationId 937404, 1 star)

• Frequency: Genomes: not found (cov: 32)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.14
• Publications: 0 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: Orphanet, Genomics England PanelApp, G2P
• gastrointestinal stromal tumor

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

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		UniProt domain with ≥4 pathogenic missense and OR ≥ 5 vs. background — hotspot (PM1); In-domain: 121 pathogenic, 13 benign rare missense variants (OR vs. background: 45.0).; ±8 AA neighbourhood: 5 pathogenic, 2 benign (OR vs. background: 11.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R46G: Pathogenic (ClinVar VariationId 12785, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R46?: Uncertain_significance (ClinVar VariationId 591278, 0 stars); p.R46P: Uncertain_significance (ClinVar VariationId 3756934, 1 star); p.R46= (synonymous): Likely_benign (ClinVar VariationId 1100244, 1 star); p.R46= (synonymous): Benign/Likely_benign (ClinVar VariationId 646758, 2 stars); p.R46= (synonymous): Likely_benign (ClinVar VariationId 937404, 1 star)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHB NM_003000.3	MANE Select	c.137_138delGAinsTG p.Arg46Leu	missense	N/A	Prot: NP_002991.2 UniProt:
	SDHB NM_001407361.1		c.137_138delGAinsTG p.Arg46Leu	missense	N/A	Prot: NP_001394290.1 UniProt:

SDHB NM_003000.3

MANE Select

HGVSc / HGVSpc.137_138delGAinsTGp.Arg46Leu

Exon rankN/A

missense

Prot: NP_002991.2UniProt: P21912

SDHB NM_001407361.1

HGVSc / HGVSpc.137_138delGAinsTGp.Arg46Leu

Exon rankN/A

missense

Prot: NP_001394290.1UniProt: A0AAQ5BHD9

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	SDHB ENST00000375499.8	TSL:1MANE Select	c.137_138delGAinsTG p.Arg46Leu	missense	N/A	Prot: ENSP00000364649.3 UniProt:
	SDHB ENST00000714034.1		c.182_183delGAinsTG p.Arg61Leu	missense	N/A	Prot: ENSP00000519325.1 UniProt:
	SDHB ENST00000925621.1		c.137_138delGAinsTG p.Arg46Leu	missense	N/A	Prot: ENSP00000595680.1 UniProt:

SDHB ENST00000375499.8

TSL:1MANE Select

HGVSc / HGVSpc.137_138delGAinsTGp.Arg46Leu

Exon rankN/A

missense

Prot: ENSP00000364649.3UniProt: P21912

SDHB ENST00000714034.1

HGVSc / HGVSpc.182_183delGAinsTGp.Arg61Leu

Exon rankN/A

missense

Prot: ENSP00000519325.1UniProt: A0AAQ5BHC9

SDHB ENST00000925621.1

HGVSc / HGVSpc.137_138delGAinsTGp.Arg46Leu

Exon rankN/A

missense

Prot: ENSP00000595680.1UniProt: A0ACI8TBD9

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	7.1

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr1-17371318;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar