Submissions for variant NM_003002.4(SDHD):c.53C>T (p.Ala18Val)

gnomAD frequency: 0.00011  dbSNP: rs192332761

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000344579	SCV000367343	likely benign	Hereditary pheochromocytoma-paraganglioma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229954	SCV000554055	uncertain significance	Carney-Stratakis syndrome; Pheochromocytoma; Paragangliomas with sensorineural hearing loss; Cowden syndrome 3	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 18 of the SDHD protein (p.Ala18Val). This variant is present in population databases (rs192332761, gnomAD 0.01%). This missense change has been observed in individual(s) with a pituitary adenoma (PMID: 25695889). ClinVar contains an entry for this variant (Variation ID: 302481). 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 95%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506525	SCV000602188	uncertain significance	not provided	2020-02-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000571997	SCV000675111	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-07	criteria provided, single submitter	clinical testing	The p.A18V variant (also known as c.53C>T) is located in coding exon 2 of the SDHD gene. The alanine at codon 18 is replaced by valine, an amino acid with similar properties. This change occurs in the first base pair of coding exon 2. This alteration has been reported in individuals with pituitary adenomas, at least one of which demonstrated loss of SDHB by IHC analysis (Xekoui et al. J. Clin. Endocrinol. Metab. 2015 May;100(5): E710-9; Hernández-Ramírez LC et al. Genet Med, 2022 Dec;24:2516-2525). This variant was also identified in a patient diagnosed with a carotid body tumor at age 48 (Sen I et al. J Vasc Surg, 2020 May;71:1602-1612.e2). However, this variant has been detected in multiple individuals with no reported features of SDHD-associated disease (Rana HQ et al. Cancers (Basel), 2024 Feb;16; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000506525	SCV001789667	uncertain significance	not provided	2025-04-10	criteria provided, single submitter	clinical testing	Observed in individuals with head/neck paraganglioma, pituitary adenoma, or other cancers (PMID: 32035780, 25695889, 36149413, 38473309); 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; This variant is associated with the following publications: (PMID: 25695889, 28873162, 32035780, 30273935, 35938916, 36149413, 38473309, 39765842)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000344579	SCV002012410	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2021-09-29	criteria provided, single submitter	clinical testing	The SDHD c.53C>T (p.Ala18Val) missense change has a maximum subpopulation frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/11-111958581-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In addition, algorithms that predict the impact of sequence changes on splicing indicate that this variant does not affect splicing. This variant has been reported in an individual with an ACTH-secreting pituitary adenoma, mild neurocognitive defects, and anxiety (PMID: 25695889, 30273935). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no evidence criteria applied.
Sema4, Sema4	RCV000571997	SCV002535345	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288968	SCV002580240	uncertain significance	Paragangliomas 1	2021-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003475929	SCV004203086	uncertain significance	Mitochondrial complex 2 deficiency, nuclear type 3	2024-03-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002288968	SCV004362299	uncertain significance	Paragangliomas 1	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 18 of the SDHD protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with head and neck paraganglioma and pituitary adenoma (PMID: 25695889, 32035780). This variant has been identified in 21/282830 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.
All of Us Research Program, National Institutes of Health	RCV000344579	SCV004815836	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 18 of the SDHD protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with head and neck paraganglioma and pituitary adenoma (PMID: 25695889, 32035780). This variant has been identified in 21/282830 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000506525	SCV001742689	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000506525	SCV001809218	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000506525	SCV001965311	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004748715	SCV005362792	uncertain significance	SDHD-related disorder	2024-05-08	no assertion criteria provided	clinical testing	The SDHD c.53C>T variant is predicted to result in the amino acid substitution p.Ala18Val. This variant was observed in an individual with an ACTH-producing pituitary adenoma; although no further evidence was provided to determine its pathogenicity (Xekouki et al. 2015. PubMed ID: 25695889). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, it is reported as likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/302481/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.