Submissions for variant NM_001735.3(C5):c.3029C>T (p.Ala1010Val)

gnomAD frequency: 0.00094  dbSNP: rs34362143

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001528281	SCV002120518	uncertain significance	not provided	2022-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1010 of the C5 protein (p.Ala1010Val). This variant is present in population databases (rs34362143, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with C5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1174632). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237878	SCV005883444	likely benign	not specified	2024-12-16	criteria provided, single submitter	clinical testing	Variant summary: C5 c.3029C>T (p.Ala1010Val) results in a non-conservative amino acid change located in the A-macroglobulin TED domain (IPR011626) 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 0.0011 in 1613786 control chromosomes in the gnomAD database, including 3 homozygotes. The observed variant frequency is approximately 10-fold of the estimated maximal expected allele frequency for a pathogenic variant in C5 causing C5 Deficiency phenotype (0.00011), providing evidence for a benign role. c.3029C>T has been reported in the literature in heterozygous individuals affected with primary immunodeficiency or unspecified neuroinflammatory disease without evidence of causality (e.g. McCreary_2019, Rudilla_2019). These reports 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 publications have been ascertained in the context of this evaluation (PMID: 31664448, 31681265). ClinVar contains an entry for this variant (Variation ID: 1174632). Based on the evidence outlined above, the variant was classified as likely benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528281	SCV001739764	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001528281	SCV001929235	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001528281	SCV001964191	likely benign	not provided		no assertion criteria provided	clinical testing