ClinVar Genomic variation as it relates to human health

Variant classified as Uncertain Significance - Favor Benign. The p.Glu163ArgfsX3 5 variant in CFHR5 (also reported as p.Glu163Arg and p.Asn197Stop) has been prev iously reported in at least two heterozygous individuals with CFHR5-deficiency a nd complement-mediated kidney diseases, as well as at least three asymptomatic i ndividuals (1 control and 2 family members of 1 of the heterozygotes; Monteferra nte 2007, Vernon 2012, and Figueres 2014). This variant has also been reported i n ClinVar (Variation ID#402534). It has been identified in 0.31% (395/126014) Eu ropean chromosomes by the Genome Aggregation Database (http://gnomad.broadinstit ute.org; rs565457964). This variant is predicted to cause a frameshift, which al ters the protein?s amino acid sequence beginning at position 163 and leads to a premature termination codon 35 amino acids downstream. This alteration is then p redicted to lead to a truncated or absent protein. In summary, while the clinica l significance of the p.Glu163ArgfsX35 variant is uncertain, these data suggest that it is more likely to be benign.

PVS1, BS1

Identified in individuals with renal disease, however, it has also been reported in clinically asymptomatic individuals (Monteferrante et al., 2007; Vernon et al., 2012; Figueres et al., 2014; Schapiro et al., 2019); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Observed in one homozygous clinically unaffected adult relative of an individual referred for genetic testing at GeneDx; Also known as c.485dupA and Asn1975Stop using alternate nomenclature; This variant is associated with the following publications: (PMID: 30295827, 31664448, 22503529, 25260719, 17000000, 31980526)

Variant summary: CFHR5 c.486dupA (p.Glu163ArgfsX35) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.002 in 251100 control chromosomes, predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 50 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFHR5 causing CFHR5 Deficiency phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.486dupA has been reported in the literature in individuals affected with CFHR5 Deficiency as well as in at least three healthy individuals (Monteferrante_2006, Vernon_2012, Figueres_2014, Benson_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), likely benign (n=1), benign (n=1) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.