Submissions for variant NM_000096.4(CP):c.1217C>A (p.Ala406Glu)

gnomAD frequency: 0.00019  dbSNP: rs147034302

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000260851	SCV000441643	uncertain significance	Deficiency of ferroxidase	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	RCV000260851	SCV000817081	uncertain significance	Deficiency of ferroxidase	2022-07-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 406 of the CP protein (p.Ala406Glu). This variant is present in population databases (rs147034302, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CP-related conditions. ClinVar contains an entry for this variant (Variation ID: 343773). 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 expected to disrupt CP 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.
Fulgent Genetics, Fulgent Genetics	RCV000260851	SCV000895543	uncertain significance	Deficiency of ferroxidase	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001770276	SCV001992744	uncertain significance	not provided	2022-07-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002520097	SCV003668080	likely benign	Inborn genetic diseases	2021-12-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Mayo Clinic Laboratories, Mayo Clinic	RCV001770276	SCV005410436	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	PM2