Submissions for variant NM_003000.3(SDHB):c.440A>G (p.Tyr147Cys)

gnomAD frequency: 0.00010  dbSNP: rs774568101

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469133	SCV000554000	uncertain significance	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 147 of the SDHB protein (p.Tyr147Cys). This variant is present in population databases (rs774568101, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of SDHB-related conditions (PMID: 28229225, 34309460; Invitae). ClinVar contains an entry for this variant (Variation ID: 412466). 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 expected to disrupt SDHB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SDHB function (PMID: 28229225). 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	RCV000492611	SCV000581187	likely benign	Hereditary cancer-predisposing syndrome	2021-09-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mendelics	RCV000708786	SCV000837735	uncertain significance	Cowden syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001294088	SCV001482894	uncertain significance	Pheochromocytoma	2019-08-24	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001755709	SCV002005149	uncertain significance	not provided	2023-05-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant may disrupt SDH cellular compartmentalization (Maignan et al., 2017); Observed in individuals with pheochromocytoma or paraganglioma (Maignan et al., 2017; Garrett et al., 2022); This variant is associated with the following publications: (PMID: 28229225, 34426522, 34906457)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282162	SCV002570738	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.440A>G (p.Tyr147Cys) results in a non-conservative amino acid change located in the Succinate dehydogenase/fumarate reductase N-terminal domain (IPR025192) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251178 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 473 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Hereditary Paraganglioma-Pheochromocytoma Syndrome phenotype (2.2e-07), strongly suggesting that the variant is benign. c.440A>G has been reported in the literature in cohorts of individuals affected with Pheochromocytoma and as a VUS in settings of multigene panel testing among individuals with Pheochromocytomas and paragangliomas (PPGLs) (example, Maignan_2017, Pipitprapat_2021) and one report published a REVEL score of 0.87 for this variant (Garrett_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Paraganglioma-Pheochromocytoma Syndrome. The following publications have been ascertained in the context of this evaluation (PMID: 28229225, 34309460, 34906457). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.