Submissions for variant NM_003000.3(SDHB):c.65G>A (p.Cys22Tyr)

dbSNP: rs141230910

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633967	SCV000755240	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 22 of the SDHB protein (p.Cys22Tyr). This variant is present in population databases (rs141230910, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with SDHB-related conditions. ClinVar contains an entry for this variant (Variation ID: 528742). 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) performed at Invitae indicates that this missense variant is not expected to disrupt SDHB 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.
Ambry Genetics	RCV002377370	SCV002667198	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-27	criteria provided, single submitter	clinical testing	The p.C22Y variant (also known as c.65G>A), located in coding exon 1 of the SDHB gene, results from a G to A substitution at nucleotide position 65. The cysteine at codon 22 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003471989	SCV004203021	uncertain significance	Gastrointestinal stromal tumor	2024-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003830	SCV004824827	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tyrosine at codon 22 of the SDHB 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 not been reported in individuals affected with SDHB-related disorders in the literature. This variant has been identified in 1/242626 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.