Submissions for variant NM_000096.4(CP):c.229G>C (p.Asp77His)

gnomAD frequency: 0.00002  dbSNP: rs200683433

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034878	SCV001219822	likely benign	Deficiency of ferroxidase	2024-11-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000034878	SCV001311844	uncertain significance	Deficiency of ferroxidase	2017-04-28	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant 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	RCV003155049	SCV003844441	uncertain significance	not specified	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: CP c.229G>C (p.Asp77His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 251164 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00014 vs 0.00019), allowing no conclusion about variant significance. c.229G>C has been reported in the literature as a presumably compound heterozygous genotype and as a non-informative genotype (second allele not specified) in at-least two individuals affected with Iron overload/Aceruloplasminemia (example, PMID: 17710675, cited in 32235485). These data do not allow any conclusion about variant significance. To our knowledge, no direct experimental evidence demonstrating an impact on protein function has been reported. Although one study characterized the variant as functionally incompetent by testing its ability to prevent ferroportin degradation in rat glioma C6 cells silenced for endogenous ceruloplasmin (example, PMID: 19095659). But the data as presented is not quantifiable into residual activity. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneReviews	RCV000034878	SCV000058484	pathologic	Deficiency of ferroxidase	2013-04-18	no assertion criteria provided	curation	Converted during submission to Pathogenic.