Submissions for variant NM_000066.4(C8B):c.1381G>T (p.Ala461Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003086082	SCV003472055	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 461 of the C8B protein (p.Ala461Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with C8B-related conditions. ClinVar contains an entry for this variant (Variation ID: 2159959). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004786828	SCV005400716	uncertain significance	Type II complement component 8 deficiency		criteria provided, single submitter	clinical testing	The observed missense c.1381G>T (p.Ala461Ser) variant in C8B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala461Ser variant is absent in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The reference amino acid of p.Ala461Ser in C8B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 461 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).