Submissions for variant NM_000063.6(C2):c.1169A>C (p.Asp390Ala)

gnomAD frequency: 0.00014  dbSNP: rs142088624

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001153972	SCV001315286	uncertain significance	Complement component 2 deficiency	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001153973	SCV001315287	uncertain significance	Age related macular degeneration 14	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032419	SCV002226214	uncertain significance	not provided	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 390 of the C2 protein (p.Asp390Ala). This variant is present in population databases (rs142088624, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with C2-related conditions. ClinVar contains an entry for this variant (Variation ID: 905443). 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) performed at Invitae indicates that this missense variant is not expected to disrupt C2 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.
Ambry Genetics	RCV004897664	SCV005549686	uncertain significance	not specified	2024-08-14	criteria provided, single submitter	clinical testing	The c.1169A>C (p.D390A) alteration is located in exon 9 (coding exon 9) of the C2 gene. This alteration results from a A to C substitution at nucleotide position 1169, causing the aspartic acid (D) at amino acid position 390 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004555615	SCV004784848	likely benign	C2-related disorder	2020-02-19	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).