NM_003000.3:c.194T>A

Variant names:

• chr1-17044767-A-T
• rs876659329
• NM_003000.3:c.194T>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_003000.3(SDHB):​c.194T>A​(p.Leu65His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 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. L65F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SDHB NM_003000.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.44
• Publications: 7 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 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 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 chr1-17044767-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 412457.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982
• PP5: Variant 1-17044767-A-T is Pathogenic according to our data. Variant chr1-17044767-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 231737.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SDHB	NM_003000.3	c.194T>A	p.Leu65His	missense_variant	Exon 2 of 8	ENST00000375499.8	NP_002991.2
SDHB	NM_001407361.1	c.194T>A	p.Leu65His	missense_variant	Exon 2 of 8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8	c.194T>A	p.Leu65His	missense_variant	Exon 2 of 8	1	NM_003000.3	ENSP00000364649.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 07, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L65H variant (also known as c.194T>A), located in coding exon 2 of the SDHB gene, results from a T to A substitution at nucleotide position 194. The leucine at codon 65 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The c.200+3G>C intronic variant results from a G to C substitution 3 nucleotides after coding exon 2 in the SDHB gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. The p.L65H alteration and the c.200+3G>C alteration have been reported in cis (same chromosome) in the germline of an individual with metastatic bladder and aortic paragangliomas. Tumor tissue from this individual contained a full length cDNA fragment including the p.L65H alteration and a cDNA fragment that was the result of exon 2 skipping (Benn DE et al. Oncogene. 2003 Mar; 22(9):1358-64). Based on the majority of available evidence to date, the p.L65H; c.200+3G>C haplotype is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.90	D;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.;.
PhyloP100		8.4
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.90
MutPred		0.83		Gain of disorder (P = 0.0214);.;.;
MVP		0.99
MPC		0.79
ClinPred		1.0	D
GERP RS		5.7
PromoterAI		-0.0026	Neutral
Varity_R		0.93
gMVP		0.85
Mutation Taster		=7/93	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: rs876659329; hg19: chr1-17371262;