Submissions for variant NM_001735.3(C5):c.989T>C (p.Ile330Thr)

gnomAD frequency: 0.00087  dbSNP: rs147430470

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262312	SCV001440131	likely benign	Complement component 5 deficiency	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001296722	SCV001485695	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 330 of the C5 protein (p.Ile330Thr). This variant is present in population databases (rs147430470, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with C5-related conditions (PMID: 37744338). ClinVar contains an entry for this variant (Variation ID: 982690). 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 C5 protein function with a negative predictive value of 80%. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001296722	SCV004160668	likely benign	not provided	2022-07-01	criteria provided, single submitter	clinical testing	C5: BP4, BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526098	SCV005040010	likely benign	not specified	2024-10-04	criteria provided, single submitter	clinical testing	Variant summary: C5 c.989T>C (p.Ile330Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 243512 control chromosomes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in C5 causing C5 Deficiency phenotype (0.00011). c.989T>C has been reported in the literature in at least one individual affected with complement-mediated atypical hemolytic uremic syndrome (e.g. Rydberg_2023). These report(s) do not provide unequivocal conclusions about association of the variant with C5 Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37744338). ClinVar contains an entry for this variant (Variation ID: 982690). Based on the evidence outlined above, the variant was classified as likely benign.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001296722	SCV002034268	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001296722	SCV002037952	likely benign	not provided		no assertion criteria provided	clinical testing