Submissions for variant NM_000096.4(CP):c.2684G>C (p.Gly895Ala)

gnomAD frequency: 0.00162  dbSNP: rs139633388

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000334692	SCV000150893	uncertain significance	not specified	2016-03-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000419016	SCV000344153	uncertain significance	not provided	2016-08-09	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000419016	SCV000511090	uncertain significance	not provided	2016-09-13	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
GeneDx	RCV000419016	SCV000564912	uncertain significance	not provided	2024-09-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G876A); This variant is associated with the following publications: (PMID: 27753142, 28968711, 18293024, 16629161, 34426522, 31785789, 33774058, 34274368, 36233161, 37784196, 32235485, 36757662)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034882	SCV000760127	likely benign	Deficiency of ferroxidase	2025-01-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000034882	SCV000895541	uncertain significance	Deficiency of ferroxidase	2018-10-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000034882	SCV001136621	uncertain significance	Deficiency of ferroxidase	2022-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000419016	SCV001247094	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	CP: PP3, BP2, BS1
Illumina Laboratory Services, Illumina	RCV000034882	SCV001311605	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	RCV000334692	SCV003844591	likely benign	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: CP c.2684G>C (p.Gly895Ala) 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 0.0015 in 250058 control chromosomes (gnomAD), predominantly at a frequency of 0.0024 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in CP causing Neurodegeneration With Brain Iron Accumulation (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. Ten ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance, one as likely pathogenic, and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
GeneReviews	RCV000034882	SCV000058488	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	RCV000034882	SCV000734248	uncertain significance	Deficiency of ferroxidase		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000419016	SCV001808578	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000419016	SCV001958203	uncertain significance	not provided		no assertion criteria provided	clinical testing
DASA	RCV001836633	SCV002097264	likely pathogenic	Hypoceruloplasminemia	2022-02-14	flagged submission	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (DOI:10.1016/j.mgene.2021.100905) - PS3_supporting. The c.2684G>C;p.(Gly895Ala) missense variant has been observed in affected individual(s) (PMID: 32235485; 27753142; 20301666; https://doi.org/10.1016/j.mgene.2021.100905) - PS4_supporting. The variant is present at low allele frequencies population databases (rs139633388 - gnomAD 0.01561%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Gly895Ala) was detected in trans with a pathogenic variant (PMID: 32235485; 27753142; https://doi.org/10.1016/j.mgene.2021.100905) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 32235485) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004745171	SCV005348419	uncertain significance	CP-related disorder	2024-07-17	no assertion criteria provided	clinical testing	The CP c.2684G>C variant is predicted to result in the amino acid substitution p.Gly895Ala. This variant has been reported in patients with aceruloplasminemia, although conclusive evidence of pathogenicity was not presented (reported as G876A in Kono et al. 2006. PubMed ID: 16629161; Vila Cuenca et al. 2020. PubMed ID: 32235485). This variant is reported in 0.25% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.