Submissions for variant NM_003000.3(SDHB):c.716C>T (p.Ser239Phe)

dbSNP: rs201098090

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000466110	SCV000554011	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-08-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 239 of the SDHB protein (p.Ser239Phe). This variant is present in population databases (rs201098090, gnomAD 0.01%). This missense change has been observed in individual(s) with metastatic paraganglioma (PMID: 18382370). ClinVar contains an entry for this variant (Variation ID: 412475). 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 expected to disrupt SDHB protein function with a positive predictive value of 80%. 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	RCV000570083	SCV000664761	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-01	criteria provided, single submitter	clinical testing	The p.S239F variant (also known as c.716C>T), located in coding exon 7 of the SDHB gene, results from a C to T substitution at nucleotide position 716. The serine at codon 239 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was identified in a patient with a personal history of metastatic paraganglioma (Klein RD et al. Diagn Mol Pathol, 2008 Jun;17:94-100). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Illumina Laboratory Services, Illumina	RCV001097530	SCV001253819	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099287	SCV001255730	uncertain significance	Carney-Stratakis syndrome	2017-04-27	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003153648	SCV003843150	uncertain significance	Paragangliomas 4	2022-11-08	criteria provided, single submitter	clinical testing	The SDHB c.716C>T (p.Ser239Phe) missense change has a maximum frequency of 0.013% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/ ). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual with metastatic paraganglioma (PMID: 18382370). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
All of Us Research Program, National Institutes of Health	RCV001097530	SCV004820493	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2024-09-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 239 of the SDHB 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). To our knowledge, functional studies have not been reported for this variant, however the residue may be structurally important (PMID: 22904323). This variant has been reported in an individual affected with paraganglioma in the literature (PMID: 18382370). This variant has been identified in 6/251464 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.
Baylor Genetics	RCV004568128	SCV005056627	uncertain significance	Gastrointestinal stromal tumor	2024-03-03	criteria provided, single submitter	clinical testing
GeneDx	RCV004760521	SCV005372711	uncertain significance	not provided	2023-07-11	criteria provided, single submitter	clinical testing	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; Identified in an individual with paraganglioma (Klein et al., 2008); This variant is associated with the following publications: (PMID: 22270996, 18382370, 26273102)