Submissions for variant NM_003000.3(SDHB):c.170A>G (p.His57Arg)

gnomAD frequency: 0.00231  dbSNP: rs35962811

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129655	SCV000184453	benign	Hereditary cancer-predisposing syndrome	2015-11-17	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	RCV001083041	SCV000287761	benign	Gastrointestinal stromal tumor; Paragangliomas 4; Pheochromocytoma	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000301812	SCV000351427	likely benign	Hereditary pheochromocytoma-paraganglioma	2018-10-15	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.
Illumina Laboratory Services, Illumina	RCV000358920	SCV000351428	likely benign	Carney-Stratakis syndrome	2018-10-15	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000122000	SCV000540303	likely benign	not specified	2016-03-28	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: 2 papers describe as non disease causing; ExAC: 0.8% (79/10404) African chromosomes; ClinVar: 3 labs classify as LB
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513898	SCV000609975	likely benign	not provided	2017-05-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513898	SCV000886094	likely benign	not provided	2018-03-22	criteria provided, single submitter	clinical testing	The SDHB c.170A>G; p.His57Arg variant is reported in the medical literature with an individual with Cowden or Cowden-like syndrome (Ni 2012), but is also reported at a greater frequency in the general population than expected for the disorder (Olfson 2015). The variant is described as benign or likely benign by several sources in the ClinVar database (Variation ID: 135192). This variant is found in the African population with an overall allele frequency of 0.8% (191/24040 alleles) in the Genome Aggregation Database. The amino acid at this position is weakly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, this variant is classified as likely benign. References: Ni Y et al. Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53. Hum Mol Genet. 2012 Jan 15;21(2):300-10. Olfson E et al. Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One. 2015 Sep 2;10(9):e0135193.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122000	SCV000918202	benign	not specified	2017-12-04	criteria provided, single submitter	clinical testing	Variant summary: The SDHB c.170A>G (p.His57Arg) variant involves the alteration of a non-conserved nucleotide located in the Succinate dehydogenase/fumarate reductase N-terminal (IPR025192) and the 2Fe-2S ferredoxin-type iron-sulfur binding domains (IPR001041) (InterPro). 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 222/278486 control chromosomes (gnomAD and Bodian_2014) at a frequency of 0.0007972, which is approximately 911 times the estimated maximal expected allele frequency of a pathogenic SDHB variant (0.0000009), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in individuals with Hereditary paraganglioma-pheochromocytoma syndrome via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign.
Sema4, Sema4	RCV000129655	SCV002527061	benign	Hereditary cancer-predisposing syndrome	2021-04-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000122000	SCV002760656	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315777	SCV004015415	benign	Paragangliomas 4	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV003315777	SCV004362280	benign	Paragangliomas 4	2022-11-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000513898	SCV005259493	likely benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000122000	SCV000086211	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148867	SCV000190611	likely benign	Cowden syndrome	2014-06-01	no assertion criteria provided	research