1-17044818-T-A

Position:

chr1-17044818-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_003000.3(SDHB):c.143A>T(p.Asp48Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,018 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D48N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

SDHB
NM_003000.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:2

Conservation

PhyloP100: 7.24

Variant links:

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 links:

SDHB (HGNC:):

SDHB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 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, 14 uncertain in NM_003000.3

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 1-17044818-T-A is Pathogenic according to our data. Variant chr1-17044818-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 39584.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=2}. Variant chr1-17044818-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SDHB	NM_003000.3 linkuse as main transcript	c.143A>T	p.Asp48Val	missense_variant	2/8	ENST00000375499.8	NP_002991.2	P21912
SDHB	NM_001407361.1 linkuse as main transcript	c.143A>T	p.Asp48Val	missense_variant	2/8		NP_001394290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SDHB	ENST00000375499.8 linkuse as main transcript	c.143A>T	p.Asp48Val	missense_variant	2/8	1	NM_003000.3	ENSP00000364649.3		P21912

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251382

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135870

show subpopulations

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:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461840

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000278

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:6Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 03, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant has only been reported/observed in association with autosomal recessive complex II deficiency and has not, to our knowledge, been associated with autosomal dominant hereditary paraganglioma/pheochromocytoma syndrome; This variant is associated with the following publications: (PMID: 22972948, 27556822, 29282712, 26642834, 27159321, 26968897, 27604842, 23174333, 29019354, 34426522, 31589614, 33726816, 26925370) -

Mitochondrial complex 2 deficiency, nuclear type 4

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2012

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 48 of the SDHB protein (p.Asp48Val). This variant is present in population databases (rs202101384, gnomAD 0.03%). This missense change has been observed in individual(s) with autosomal recessive mitochondrial complex II deficiency (PMID: 22972948, 26642834, 26925370, 27604842). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 39584). 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 not expected to disrupt SDHB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 22972948). For these reasons, this variant has been classified as Pathogenic. -

Paragangliomas 4

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

This sequence change replaces aspartic acid with valine at codon 48 of the SDHB protein (p.Asp48Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs202101384, ExAC 0.04%). This variant has been observed as homozygous or in combination with other SDHB variant in individuals affected with autosomal recessive mitochondrial complex II deficiency (PMID: 22972948, 27556822, 29282712, 26642834, 27159321, 26968897, 27604842, 23174333, 29019354, 34426522, 31589614, 33726816, 26925370). However, this variant has not been observed in individuals with pheochromocytoma (PCC) or paraganglioma (PGL). ClinVar contains an entry for this variant (Variation ID: 39584). In silico analysis supports that this missense variant has a deleterious effect on protein structure/function also an experimental study shown the affected protein function . In summary, this variant has been observed in individuals with mitochondrial complex II deficiency and has been shown to affect protein function. The currently available evidence indicates that the variant is pathogenic, Therefore, this variant has been classified as Likely Pathogenic. -

Gastrointestinal stromal tumor

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 04, 2023

- -

Mitochondrial complex II deficiency, nuclear type 1

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2024

The p.D48V variant (also known as c.143A>T), located in coding exon 2 of the SDHB gene, results from an A to T substitution at nucleotide position 143. The aspartic acid at codon 48 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been detected in both the homozygous and compound heterozygous states with a second SDHB variant in multiple individuals with features of mitochondrial complex II deficiency (Alston CL et al. J. Med. Genet., 2012 Sep;49:569-77; Ardissone A et al. Mol Genet Metab Rep, 2015 Dec;5:51-54; Helman G et al. Ann. Neurol., 2016 Mar;79:379-86; Vanderver A et al. Ann Neurol, 2016 06;79:1031-1037; Grønborg S et al. JIMD Rep, 2017 Sep;33:69-77). Functional studies showed reduced SDHB and complex II in tissues and cells from affected individuals (Alston CL et al. J. Med. Genet., 2012 Sep;49:569-77; Ardissone A et al. Mol Genet Metab Rep, 2015 Dec;5:51-54; Grønborg S et al. JIMD Rep, 2017 Sep;33:69-77). To our knowledge, this variant has not been detected in individuals with a paraganglioma or pheochromocytoma. 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 variant is expected to be causative of autosomal recessive mitochondrial complex II deficiency when present along with a second likely pathogenic/pathogenic variant on the other allele; however, its clinical significance for autosomal dominant paraganglioma-pheochromocytoma syndrome is unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.84

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.0

D;.

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.89

P;.

Vest4

0.94

MutPred

0.54

Gain of MoRF binding (P = 0.0286);.;

MVP

0.99

MPC

0.73

ClinPred

0.93

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.93

gMVP

0.87

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over