Submissions for variant NM_003000.3(SDHB):c.130A>G (p.Ile44Val)

gnomAD frequency: 0.00002  dbSNP: rs200418115

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521448	SCV000617701	uncertain significance	not provided	2020-06-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693783	SCV000821665	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 44 of the SDHB protein (p.Ile44Val). This variant is present in population databases (rs200418115, gnomAD 0.009%). 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: 449495). 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 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	RCV001010888	SCV001171144	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-13	criteria provided, single submitter	clinical testing	The p.I44V variant (also known as c.130A>G), located in coding exon 2 of the SDHB gene, results from an A to G substitution at nucleotide position 130. The isoleucine at codon 44 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, valine is the reference amino acid in other vertebrate species. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002268138	SCV002552263	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003476220	SCV004202964	uncertain significance	Gastrointestinal stromal tumor	2023-11-11	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003602	SCV004831049	uncertain significance	Hereditary pheochromocytoma-paraganglioma	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 44 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 10/251358 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.
PreventionGenetics, part of Exact Sciences	RCV004732924	SCV005366206	uncertain significance	SDHB-related disorder	2024-06-06	no assertion criteria provided	clinical testing	The SDHB c.130A>G variant is predicted to result in the amino acid substitution p.Ile44Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/449495/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.