Submissions for variant NM_003000.3(SDHB):c.158G>A (p.Gly53Glu)

gnomAD frequency: 0.00041  dbSNP: rs34916635

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163315	SCV000213843	benign	Hereditary cancer-predisposing syndrome	2015-09-06	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Invitae	RCV001081765	SCV000261941	benign	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000266464	SCV000351429	likely benign	Carney-Stratakis syndrome	2019-04-21	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.
Illumina Laboratory Services, Illumina	RCV000323978	SCV000351430	likely benign	Hereditary pheochromocytoma-paraganglioma	2019-04-21	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
GeneDx	RCV000713176	SCV000730537	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23512077, 25694510, 21979946, 25394176, 19802898, 18458953, 23072324, 20923864, 28873162, 30152102)
Athena Diagnostics	RCV000713176	SCV000843759	benign	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000602372	SCV001478595	benign	not specified	2021-01-17	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.158G>A (p.Gly53Glu) results in a non-conservative amino acid change located in the 2Fe-2S ferredoxin-type iron-sulfur binding domain (IPR010141) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00053 in 251378 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is higher than 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. Although, this variant has been reported in the literature (example, Fishbein_2013, Cox_2018), to our knowledge, no occurrence of c.158G>A in individuals affected with Hereditary Paraganglioma-Pheochromocytoma Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=3)/likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000163315	SCV002527060	benign	Hereditary cancer-predisposing syndrome	2021-07-15	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000602372	SCV002552241	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000713176	SCV004220332	benign	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003514320	SCV004362281	benign	Paragangliomas 4	2022-09-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713176	SCV004700590	benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	SDHB: BS1, BS2
PreventionGenetics, part of Exact Sciences	RCV004535070	SCV004743598	likely benign	SDHB-related disorder	2020-07-13	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
GenomeConnect, ClinGen	RCV000709876	SCV000840213	not provided	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Cowden syndrome 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.