Submissions for variant NM_003000.3(SDHB):c.8C>G (p.Ala3Gly)

gnomAD frequency: 0.01309  dbSNP: rs11203289

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128921	SCV000172790	benign	Hereditary cancer-predisposing syndrome	2014-12-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079357	SCV000261805	benign	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2025-02-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000368190	SCV000351451	benign	Carney-Stratakis syndrome	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000275977	SCV000351452	benign	Hereditary pheochromocytoma-paraganglioma	2018-03-06	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
GeneDx	RCV000121999	SCV000514599	benign	not specified	2016-11-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000121999	SCV000540300	benign	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034690	SCV000610498	benign	not provided	2017-04-19	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000121999	SCV000859747	benign	not specified	2018-03-04	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755699	SCV000883132	benign	Paragangliomas 4	2018-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000986270	SCV001135209	likely benign	Gastrointestinal stromal tumor	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000121999	SCV001363919	benign	not specified	2019-12-23	criteria provided, single submitter	clinical testing	Variant summary: SDHB c.8C>G (p.Ala3Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0031 in 242034 control chromosomes in the gnomAD database, including 19 homozygotes. The observed variant frequency is approximately over 3000 fold of the estimated maximal expected allele frequency for a pathogenic variant in SDHB causing Pheochromocytoma phenotype (8.8e-07), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.8C>G in individuals affected with Pheochromocytoma and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign, n=7). Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034690	SCV001473226	benign	not provided	2023-10-11	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128921	SCV002527093	benign	Hereditary cancer-predisposing syndrome	2020-04-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000121999	SCV002552285	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490359	SCV002804110	likely benign	Gastrointestinal stromal tumor; Carney-Stratakis syndrome; Paragangliomas 4; Pheochromocytoma; Mitochondrial complex 2 deficiency, nuclear type 4	2022-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034690	SCV004123318	benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	SDHB: BS1, BS2
Color Diagnostics, LLC DBA Color Health	RCV000755699	SCV004362288	benign	Paragangliomas 4	2022-06-09	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000034690	SCV005259526	likely benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000013632	SCV000033879	uncertain significance	Cowden syndrome	2008-08-01	no assertion criteria provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034690	SCV000043487	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000121999	SCV000086210	not provided	not specified	2013-09-19	no assertion provided	reference population
PreventionGenetics, part of Exact Sciences	RCV004532333	SCV004740826	benign	SDHB-related disorder	2020-01-15	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).