rs149516118

chr11-112087962-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_003002.4(SDHD):c.158C>T(p.Pro53Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,604,708 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P53A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

SDHD
NM_003002.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 3.35

Variant links:

Genes affected

SDHD (HGNC:10683): (succinate dehydrogenase complex subunit D) This gene encodes a member of complex II of the respiratory chain, which is responsible for the oxidation of succinate. The encoded protein is one of two integral membrane proteins anchoring the complex to the matrix side of the mitochondrial inner membrane. Mutations in this gene are associated with the formation of tumors, including hereditary paraganglioma. Transmission of disease occurs almost exclusively through the paternal allele, suggesting that this locus may be maternally imprinted. There are pseudogenes for this gene on chromosomes 1, 2, 3, 7, and 18. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2013]

SDHD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SDHD	NM_003002.4 linkuse as main transcript	c.158C>T	p.Pro53Leu	missense_variant	2/4	ENST00000375549.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SDHD	ENST00000375549.8 linkuse as main transcript	c.158C>T	p.Pro53Leu	missense_variant	2/4	1	NM_003002.4	P1	O14521-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251434

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1452530

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

723322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000163

Gnomad4 OTH exome

AF:

0.0000998

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000237

Hom.:

Bravo

AF:

0.0000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 09, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 30, 2023	Observed in individuals with paraganglioma or pheochromocytoma, co-occurring with a truncating SDHB variant in one case (Lefebvre et al., 2012; Ben Aim et al., 2019; Donato et al., 2019); Co-segregated with a truncating SDHD variant in several relatives affected with paraganglioma in one family (Leidenz et al., 2015); Published functional studies are inconclusive: showed minimal to no effect on SDH activity and function, but a known pathogenic variant in SDHD performed similarly (Panizza et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 22517554, 25637381, 25985138, 30877234, 31104306, 32659967, 25819804, 23175444) -

Pheochromocytoma;C1847319:Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss;CN166604:Cowden syndrome 3

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 53 of the SDHD protein (p.Pro53Leu). This variant is present in population databases (rs149516118, gnomAD 0.01%). This missense change has been observed in individual(s) with hereditary paraganglioma pheochromocytoma syndrome and sporadic pheochromocytoma and paraganglioma (PMID: 22517554, 25819804, 30877234). ClinVar contains an entry for this variant (Variation ID: 161388). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SDHD protein function. Experimental studies have shown that this missense change does not substantially affect SDHD function (PMID: 23175444). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Pheochromocytoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 12, 2023

The p.P53L variant (also known as c.158C>T), located in coding exon 2 of the SDHD gene, results from a C to T substitution at nucleotide position 158. The proline at codon 53 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in individuals with sporadic pheochromocytoma and/or paraganglioma (Lefebvre S et al, Horm. Metab. Res. 2012 May; 44(5):334-8; Donato S et al. Endocrine 2019 08;65(2):408-415). This alteration has also been seen in an individual with a locally advanced paraganglioma, large bilateral carotid body tumors and family history of cervical masses in his five siblings; however, this proband was shown to carry an additional germline nonsense alteration in the SDHD gene (p.Trp5*), which also segregated with p.P53L in all affected family members (Leidenz FB et al, Genet Res (Camb) 2015; 97:e3). A yeast based functional assay has shown this alteration resulted in no/mild phenotypic effect on oxidative growth (Panizza E et al, Hum. Mol. Genet. 2013 Feb; 22(4):804-15). This alteration was also reported as an incidental finding in individuals from whole genome and whole exome sequencing (Amendola LM et al, Genome Res. 2015 Mar; 25(3):305-15; Taylor JC et al. Nat. Genet. 2015 Jul;47(7):717-726).This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -

Hereditary pheochromocytoma-paraganglioma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 30, 2023

This missense variant replaces proline with leucine at codon 53 of the SDHD 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). Functional studies have shown that this variant complemented a yeast SDHD null mutant for oxidative growth phenotype and displaying 70% succinate dehydrogenase protein activity (PMID: 23175444). This variant has been reported individuals affected with paragangliomas/pheochrocytomas (PMID: 22517554, 25819804, 30877234, 31104306). In one PGL/PCC family, this variant was likely in cis with a truncating SDHD variant (c.14G>A; p.Trp5X) in multiple affected carriers (PMID: 25819804). In another individual affected with paraganglioma this variant co-occurred with a truncating SDHB variant (c.435del; Phe146SerfsX12; PMID: 30877234). This variant has also been reported in an individual affected with sarcoma and adenocarcinoma (PMID: 32659967). This variant has been identified in 12/282828 chromosomes 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. -

Carney-Stratakis syndrome;C1868633:Paragangliomas with sensorineural hearing loss

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

Variant interpreted as Uncertain significance and reported on 07-11-2017 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.44

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.61

D;.;.;.;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.71

T;T;T;T;T;.

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.76

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.8

M;M;.;M;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.8

N;.;N;D;N;N

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0050

D;.;D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D;D;D

Polyphen

1.0

D;.;.;.;.;.

Vest4

0.54

MVP

0.97

MPC

0.27

ClinPred

0.66

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.094

gMVP

0.65

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.26

Position offset: 11

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