Submissions for variant NM_030787.4(CFHR5):c.486dup (p.Glu163fs)

dbSNP: rs565457964

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455834	SCV000538667	uncertain significance	not specified	2017-10-18	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000767072	SCV000568842	uncertain significance	not provided	2020-07-01	criteria provided, single submitter	clinical testing	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)
Invitae	RCV000767072	SCV001028978	likely benign	not provided	2024-01-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000030802	SCV001135489	benign	CFHR5 deficiency	2019-05-28	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV001171343	SCV001328290	uncertain significance	Chronic kidney disease	2020-05-28	criteria provided, single submitter	research	PVS1, BS1
Mayo Clinic Laboratories, Mayo Clinic	RCV000767072	SCV001715641	uncertain significance	not provided	2021-11-30	criteria provided, single submitter	clinical testing
Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000030802	SCV001984583	uncertain significance	CFHR5 deficiency	2020-03-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000455834	SCV002074527	uncertain significance	not specified	2022-01-04	criteria provided, single submitter	clinical testing	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.
Revvity Omics, Revvity	RCV000030802	SCV003831622	uncertain significance	CFHR5 deficiency	2021-08-06	criteria provided, single submitter	clinical testing
OMIM	RCV000030802	SCV000053471	pathogenic	CFHR5 deficiency	2012-07-01	no assertion criteria provided	literature only