Submissions for variant NM_000096.4(CP):c.2158C>T (p.Arg720Trp)

gnomAD frequency: 0.00025  dbSNP: rs145784949

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000441214	SCV000511539	uncertain significance	not provided	2016-09-13	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Invitae	RCV000034950	SCV000823397	uncertain significance	Deficiency of ferroxidase	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 720 of the CP protein (p.Arg720Trp). This variant is present in population databases (rs145784949, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of aceruloplasminemia (PMID: 15654567, 29482220). ClinVar contains an entry for this variant (Variation ID: 42123). 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 CP protein function. Experimental studies have shown that this missense change affects CP function (PMID: 19095659, 20430895, 20655381, 22281056). 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	RCV000034950	SCV000895542	uncertain significance	Deficiency of ferroxidase	2021-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000034950	SCV001310079	uncertain significance	Deficiency of ferroxidase	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222363	SCV002500790	uncertain significance	not specified	2023-05-24	criteria provided, single submitter	clinical testing	Variant summary: CP c.2158C>T (p.Arg720Trp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 251422 control chromosomes. The observed variant frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation phenotype (0.00019). c.2158C>T has been reported in the literature in heterozygous individuals (without a known pathogenic variant detected in trans) affected with aceruloplasminemia, but it was also reported in their unaffected heterozygous parents (Kuhn_2005 and Hines_2018). These reports do not provide unequivocal conclusions about association of the variant with Neurodegeneration With Brain Iron Accumulation. The variant has been reported to confer a dominant negative effect over wild type Cp (di Patti_2009). Experimental evidence from cell culture models demonstrated that it correctly reaches the plasma membrane, but fails to stabilize ferroportin on cell surface due to inherently impaired oxidase activity. It was further shown to induce fragmentation/dispersal of the Golgi apparatus and impair the proper functioning of ATP7B, which becomes unable to discharge copper into the target ferroxidase; these effects being accompanied by the massive production of reactive oxygen species in the cell (e.g. di Patti_2009, Kono_2010, Maio_2010, Persichini_2012). The following publications have been ascertained in the context of this evaluation (PMID: 29482220, 20655381, 15654567, 20430895, 22281056, 19095659). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneReviews	RCV000034950	SCV000058570	pathologic	Deficiency of ferroxidase	2013-04-18	no assertion criteria provided	curation	Converted during submission to Pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000441214	SCV001741190	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000441214	SCV001809174	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000441214	SCV001963869	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000441214	SCV002037542	uncertain significance	not provided		no assertion criteria provided	clinical testing