Submissions for variant NM_000064.4(C3):c.1645G>A (p.Asp549Asn)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003560071	SCV004297989	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change affects C3 function (PMID: 7961791). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on C3 protein function. This missense change has been observed in individual(s) with C3 deficiency (PMID: 7961791). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 549 of the C3 protein (p.Asp549Asn).
Clinical Genomics Laboratory, Washington University in St. Louis	RCV005052060	SCV005685206	uncertain significance	Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency	2024-05-23	criteria provided, single submitter	clinical testing	The C3 c.1645G>A (p.Asp549Asn) variant was identified. The C3 c.1645G>A (p.Asp549Asn) variant has been reported in a heterozygous state in one family affected with C3 deficiency (Okura Y et al., PMID: 26435005; Singer L et al., PMID: 7961791). This variant is only observed on 5/1,613,400 alleles in the general population (gnomAD v.4.1.0), indicating it is not a common variant. This variant has been reported in the ClinVar database as a variant of uncertain significance by one submitter (ClinVar ID: 2736765). Computational predictors are uncertain as to the impact of this variant on C3 function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.