ClinVar Genomic variation as it relates to human health

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

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.

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.

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.

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.

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.