Submissions for variant NM_003002.4(SDHD):c.158C>T (p.Pro53Leu)

gnomAD frequency: 0.00003  dbSNP: rs149516118

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002228536	SCV000640146	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2025-01-30	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SDHD protein function with a negative predictive value of 80%. 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 (internal data). 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.
Ambry Genetics	RCV000562737	SCV000675118	uncertain significance	Hereditary cancer-predisposing syndrome	2025-02-07	criteria provided, single submitter	clinical testing	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 diagnosed 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 amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759346	SCV000888624	uncertain significance	not provided	2018-07-09	criteria provided, single submitter	clinical testing
GeneDx	RCV000759346	SCV001830903	uncertain significance	not provided	2024-01-29	criteria provided, single submitter	clinical testing	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)
All of Us Research Program, National Institutes of Health	RCV003998178	SCV004845793	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-09-23	criteria provided, single submitter	clinical testing	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.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000562737	SCV005902118	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-27	criteria provided, single submitter	clinical testing	PP3_Moderate c.158C>T, located in exon 2 of the SDHD gene, is predicted to result in the substitution of proline by leucine at codon 30, p.(Pro53Leu).This variant is found in 4/34260, with a filter allele frequency of 0.002% at 99% confidence in the gnomAD v2.1.1 database (Latino non-cancer data set). The SpliceAI algorithm results in a non-informative deltascore (0.25) for the effect of this variant on splicing and the REVEL meta-predictor score (0.778) for this variant suggests a deleterious effect on protein function according to Pejaver 2022 thresholds (PMID: 36413997) (PP3_Moderate). Functional studies have shown that this missense change does not affect SDHD function substantially (PMID:23175444). It has been reported in ClinVar (5x uncertain significance) and LOVD (3x uncertain significance) databases. It has been identified in an individual with paraganglioma where another pathogenic variant in SDHD has also been identified in trans (PMID: 25819804) and in patients from our internal cohort showing other several cancer types (ovarian , breast, colorectal, prostate,…). Based on currently available information, c.158C>T is classified as an uncertain significance variant according to ACMG guidelines.
Color Diagnostics, LLC DBA Color Health	RCV003998178	SCV006064909	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-10-15	criteria provided, single submitter	clinical testing	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. 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.
CSER _CC_NCGL, University of Washington	RCV000148873	SCV000190617	uncertain significance	Pheochromocytoma	2014-06-01	no assertion criteria provided	research
GenomeConnect - Invitae Patient Insights Network	RCV003483523	SCV004228763	not provided	Carney-Stratakis syndrome; Paragangliomas with sensorineural hearing loss		no assertion provided	phenotyping only	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.