ClinVar Genomic variation as it relates to human health
NM_003002.4(SDHD):c.158C>T (p.Pro53Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_003002.4(SDHD):c.158C>T (p.Pro53Leu)
Variation ID: 161388 Accession: VCV000161388.24
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 11q23.1 11: 112087962 (GRCh38) [ NCBI UCSC ] 11: 111958686 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 7, 2014 Sep 16, 2024 Jan 31, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_003002.4:c.158C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_002993.1:p.Pro53Leu missense NM_001276503.2:c.158C>T NP_001263432.1:p.Pro53Leu missense NM_001276504.2:c.53-905C>T intron variant NM_001276506.2:c.158C>T NP_001263435.1:p.Pro53Leu missense NR_077060.2:n.193C>T non-coding transcript variant NC_000011.10:g.112087962C>T NC_000011.9:g.111958686C>T NG_012337.3:g.6116C>T NG_033145.1:g.3837G>A LRG_9:g.6116C>T LRG_9t1:c.158C>T LRG_9p1:p.Pro53Leu - Protein change
- P53L
- Other names
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- Canonical SPDI
- NC_000011.10:112087961:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00004
Exome Aggregation Consortium (ExAC) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SDHD | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
657 | 798 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148873.11 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 12, 2023 | RCV000562737.13 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jan 29, 2024 | RCV000759346.17 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 31, 2024 | RCV002228536.12 | |
not provided (1) |
no classification provided
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- | RCV003483523.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 30, 2023 | RCV003998178.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Jul 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000888624.2
First in ClinVar: Mar 14, 2019 Last updated: Jan 01, 2022 |
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Uncertain significance
(Jan 31, 2024)
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criteria provided, single submitter
Method: clinical testing
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Carney-Stratakis syndrome
Paragangliomas with sensorineural hearing loss Pheochromocytoma Cowden syndrome 3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000640146.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
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Uncertain Significance
(Nov 30, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary pheochromocytoma-paraganglioma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004845793.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Jan 12, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000675118.6
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
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Uncertain significance
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001830903.5
First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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) (less)
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Phaeochromocytoma
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190617.1 First in ClinVar: Dec 07, 2014 Last updated: Dec 07, 2014
Comment:
Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript
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not provided
(-)
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no classification provided
Method: phenotyping only
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Paragangliomas with sensorineural hearing loss
Carney-Stratakis syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228763.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Breast carcinoma (present)
Indication for testing: Diagnostic
Age: 30-39 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Invitae
Date variant was reported to submitter: 2017-07-11
Testing laboratory interpretation: Uncertain significance
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical and Molecular Assessment of Patients with Lynch Syndrome and Sarcomas Underpinning the Association with MSH2 Germline Pathogenic Variants. | de Angelis de Carvalho N | Cancers | 2020 | PMID: 32659967 |
SDHx-related pheochromocytoma/paraganglioma - genetic, clinical, and treatment outcomes in a series of 30 patients from a single center. | Donato S | Endocrine | 2019 | PMID: 31104306 |
Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. | Ben Aim L | Journal of medical genetics | 2019 | PMID: 30877234 |
Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. | Taylor JC | Nature genetics | 2015 | PMID: 25985138 |
Malignant phenotype and two SDHD mutations in a family with paraganglioma syndrome type 1. | Leidenz FB | Genetics research | 2015 | PMID: 25819804 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Yeast model for evaluating the pathogenic significance of SDHB, SDHC and SDHD mutations in PHEO-PGL syndrome. | Panizza E | Human molecular genetics | 2013 | PMID: 23175444 |
Screening of mutations in genes that predispose to hereditary paragangliomas and pheochromocytomas. | Lefebvre S | Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme | 2012 | PMID: 22517554 |
Text-mined citations for rs149516118 ...
HelpRecord last updated Oct 13, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.