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

gnomAD frequency: 0.00003  dbSNP: rs386134127

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237457	SCV002041880	likely pathogenic	Neurodegeneration with brain iron accumulation	2024-12-18	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 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 (gnomAD). c.1049C>A (aka. A331D) has been reported in the homozygous state in the literature in multiple individuals affected with clinical or laboratory features of Neurodegeneration With Brain Iron Accumulation (examples, Perez-Aguilar_2005, Kassubek_2017), including at least 1 family where this variant segregated with near complete absence of detectable ceruloplasmin in serum. These data indicate that the variant is likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function and demonstrated that the variant protein was retained in the endoplasmic reticulum, presumably due to misfolding (Kono_2010), furthermore indirect evidence indicated a partial ferroxidase activity (di Patti_2009). The following publications have been ascertained in the context of this evaluation (PMID: 28431603, 20655381, 15885371, 32235485, 19095659). ClinVar contains an entry for this variant (Variation ID: 42047). Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneReviews	RCV000034876	SCV000058482	pathologic	Deficiency of ferroxidase	2013-04-18	no assertion criteria provided	curation	Converted during submission to Pathogenic.