ClinVar Miner

Submissions for variant NM_000096.4(CP):c.1049C>A (p.Ala350Asp)

gnomAD frequency: 0.00003  dbSNP: rs386134127
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797595 SCV002041880 uncertain significance not specified 2021-11-08 criteria provided, single submitter clinical testing Variant summary: CP c.1049C>A (p.Ala350Asp) results in a non-conservative amino acid change located in the Multicopper oxidase, type 1 domain (IPR001117) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251124 control chromosomes. c.1049C>A has been reported in the literature as a homozygous genotype in at-least three individuals, two of whom were sibs, affected with features of Neurodegeneration With Brain Iron Accumulation secondary to a laboratory diagnosis of Aceruloplasminemia (example, Perez-Aguilar_2005, Kassubek_2017). The first case report of the siblings noted the index case as being a 39 year old asymptomatic man with characteristic laboratory and supportive T2 weighted MRI findings (Perez-Aguilar_2005). The subsequent case report involving a 72 year old female with a depressive disorder demonstrated similar laboratory and MRI findings with acanthocytosis (Kassubek_2017). These data indicate that the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, however, do not allow convincing conclusions about the variant effect based on the data presented (example, Kono_2010, di Patti_2009). Direct Ferroxidase activity levels are not reported in both publications. Although one study demonstrates that mutant A331D (legacy name for this variant) is retained in the Endoplasmic Reticulum, presumably from misfolding of the protein (Kono_2010), the other provides an indirect evidence for partial Ferroxidase activity (di Patti_2009). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
GeneReviews RCV000034876 SCV000058482 pathologic Deficiency of ferroxidase 2013-04-18 no assertion criteria provided curation Converted during submission to Pathogenic.

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