Submissions for variant NM_000064.4(C3):c.4148C>A (p.Thr1383Asn)

gnomAD frequency: 0.00011  dbSNP: rs139100972

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001131705	SCV001291340	benign	Atypical hemolytic-uremic syndrome with C3 anomaly	2017-04-28	criteria provided, single submitter	clinical testing	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 rule this variant out of causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001131706	SCV001291341	uncertain significance	Complement component 3 deficiency	2017-04-28	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001131707	SCV001291342	uncertain significance	Age related macular degeneration 9	2017-04-28	criteria provided, single submitter	clinical testing	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000782234	SCV002185496	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1383 of the C3 protein (p.Thr1383Asn). This variant is present in population databases (rs139100972, gnomAD 0.04%). This missense change has been observed in individual(s) with atypical hemolytic uremic syndrome (PMID: 20595690, 25608561, 28752844, 32424742). This variant is also known as T1361N. ClinVar contains an entry for this variant (Variation ID: 633670). 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) has been performed 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. Experimental studies have shown that this missense change does not substantially affect C3 function (PMID: 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.
Fulgent Genetics, Fulgent Genetics	RCV005021172	SCV005647529	uncertain significance	Age related macular degeneration 9; Atypical hemolytic-uremic syndrome with C3 anomaly; Complement component 3 deficiency	2024-01-14	criteria provided, single submitter	clinical testing
Gharavi Laboratory, Columbia University	RCV000782234	SCV000920723	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research