rs149516118
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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 (★★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 0 hom. )
Consequence
SDHD
NM_003002.4 missense
NM_003002.4 missense
Scores
6
8
5
Clinical Significance
Conservation
PhyloP100: 3.35
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]
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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 | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SDHD | NM_003002.4 | c.158C>T | p.Pro53Leu | missense_variant | 2/4 | ENST00000375549.8 | NP_002993.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SDHD | ENST00000375549.8 | c.158C>T | p.Pro53Leu | missense_variant | 2/4 | 1 | NM_003002.4 | ENSP00000364699.3 | ||
| ENSG00000255292 | ENST00000532699.1 | n.158C>T | non_coding_transcript_exon_variant | 2/6 | 3 | ENSP00000456434.1 |
Frequencies
GnomAD3 genomes 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251434Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135902
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GnomAD4 exome AF: 0.0000234 AC: 34AN: 1452530Hom.: 0 Cov.: 28 AF XY: 0.0000263 AC XY: 19AN XY: 723322
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GnomAD4 genome 0.0000329 AC: 5AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74334
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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 | Jan 29, 2024 | Observed in individuals with paraganglioma or pheochromocytoma, co-occurring with a truncating SDHB variant in one case (PMID: 22517554, 30877234, 31104306); Co-segregated with a truncating SDHD variant in several relatives affected with paraganglioma in one family (PMID: 25819804); Published functional studies are inconclusive: showed minimal to no effect on SDH activity and function, but a known pathogenic variant in SDHD performed similarly (PMID: 23175444); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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 | Labcorp Genetics (formerly Invitae), Labcorp | 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 | Sep 23, 2024 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;.;M;.;M
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;D;N;N
REVEL
Pathogenic
Sift
Uncertain
D;.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;.;.;.;.;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 11
Find out detailed SpliceAI scores and Pangolin per-transcript scores at