Submissions for variant NM_000064.4(C3):c.193A>C (p.Lys65Gln)

gnomAD frequency: 0.00005  dbSNP: rs539992721

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000427027	SCV000521327	uncertain significance	not provided	2024-04-29	criteria provided, single submitter	clinical testing	Reported multiple times in the heterozygous state in possible association with atypical hemolytic-uremic syndrome, however, detailed clinical and segregation information was not provided in all instances (PMID: 22669319, 25899302, 30046676, 34169201, 33841858); Published functional studies demonstrate that this alteration leads to decreased binding of C3b to CFH in vitro and modest but significant decreases in factor F and membrane cofactor protein association rate and binding affinity compared to wild type (PMID: 22669319, 25608561); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22669319, 36631797, 37744338, 25608561, 24736606, 31589614, 30046676, 33609329, 25899302, 34169201, 33841858, 37567446, 35385571, 32765494, 29888403, 24799305, 23852337, 28025630, 24853370, 25188723, 24038559, 30225264, 34631043)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000427027	SCV002298601	uncertain significance	not provided	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 65 of the C3 protein (p.Lys65Gln). This variant is present in population databases (rs539992721, gnomAD 0.009%). This missense change has been observed in individuals with atypical hemolytic uremic syndrome (PMID: 22669319, 25608561, 30046676, 33609329, 35372954). This variant is also known as K43Q. ClinVar contains an entry for this variant (Variation ID: 381739). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt C3 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects C3 function (PMID: 22669319, 25608561). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003138002	SCV003807907	likely pathogenic	Complement component 3 deficiency	2022-08-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 supporting
Baylor Genetics	RCV003147456	SCV003836277	likely pathogenic	Atypical hemolytic-uremic syndrome with C3 anomaly	2022-02-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003138002	SCV003836278	likely pathogenic	Complement component 3 deficiency	2022-02-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147457	SCV003836302	likely pathogenic	Age related macular degeneration 9	2022-02-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320186	SCV004024318	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005018727	SCV005648796	likely pathogenic	Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency	2024-05-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003320186	SCV005885324	uncertain significance	not specified	2025-02-24	criteria provided, single submitter	clinical testing	Variant summary: C3 c.193A>C (p.Lys65Gln) results in a conservative amino acid change located in the MG2 domain of 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 4.8e-05 in 251474 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in C3 causing C3 Deficiency (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.193A>C has been reported in the literature in multiple heterozygous individuals affected with atypical Haemolytic uraemic syndrome without strong evidence of segregation (examples: Volokhina_2012, Duvvari_2014, Fidalgo_2017, Wilson_2020, Akesson_2021, Ardissino_2021). These report(s) do not provide unequivocal conclusions about association of the variant with C3 Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Volokhina_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22669319, 24736606, 30046676, 35372954, 33609329, : 34169201). ClinVar contains an entry for this variant (Variation ID: 381739). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328274	SCV001449196	pathogenic	Atypical hemolytic-uremic syndrome	2018-08-28	no assertion criteria provided	clinical testing	This patient is heterozygous for a known pathogenic variant, c.193A>C (p.Lys65Gln), in the C3 gene. This variant (dbSNP: rs539992721) has been reported in the Exome Aggregation Consortium (ExAC) database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.006% (7/121402 alleles). This variant is reported in the C3 aHUS mutation database (www.fh-hus.org/) including three atypical haemolytic uremic syndrome (aHUS) patients whom acquired the illness as an adult, with first aHUS episode after renal transplantation or suffered recurrence of the disease after renal transplantation (Volokhina et al 2012 Pediatr Nephrol 27:1519-1524). The authors also performed functional studies which showed the C3 mutant protein decreases C3b binding to CFH in vitro.