Submissions for variant NM_014324.6(AMACR):c.554T>C (p.Val185Ala)

gnomAD frequency: 0.00084  dbSNP: rs145786819

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224246	SCV000281027	likely benign	not provided	2016-01-29	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Eurofins Ntd Llc (ga)	RCV000224246	SCV000708653	uncertain significance	not provided	2017-11-21	criteria provided, single submitter	clinical testing
Invitae	RCV000706283	SCV000835323	uncertain significance	Alpha-methylacyl-CoA racemase deficiency	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 185 of the AMACR protein (p.Val185Ala). This variant is present in population databases (rs145786819, gnomAD 0.2%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of AMACR-related conditions (PMID: 20818383, 25133958). ClinVar contains an entry for this variant (Variation ID: 235439). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000224246	SCV001154382	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000706283	SCV001318166	uncertain significance	Alpha-methylacyl-CoA racemase deficiency	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). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224246	SCV001714141	uncertain significance	not provided	2019-10-14	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224246	SCV002047944	uncertain significance	not provided	2021-11-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003407763	SCV004115078	uncertain significance	AMACR-related disorder	2023-08-11	criteria provided, single submitter	clinical testing	The AMACR c.554T>C variant is predicted to result in the amino acid substitution p.Val185Ala. This variant was reported in an individual with complex I deficiency and an individual with ataxia (Table S2, Calvo et al. 2010. PubMed ID: 20818383; Table 2, Fogel et al. 2014. PubMed ID: 25133958). This variant is reported in 0.15% of alleles in individuals of South Asian descent in gnomAD, including a homozygous observation (http://gnomad.broadinstitute.org/variant/5-33998931-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.