Submissions for variant NM_000666.3(ACY1):c.575dup (p.Ser192fs)

gnomAD frequency: 0.00014  dbSNP: rs770702363

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001091093	SCV001246944	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV001091093	SCV001714106	pathogenic	not provided	2019-04-07	criteria provided, single submitter	clinical testing	PVS1, PS3, PM2, PM3, PP4
Fulgent Genetics, Fulgent Genetics	RCV000984988	SCV002784487	pathogenic	Aminoacylase 1 deficiency	2021-08-26	criteria provided, single submitter	clinical testing
Invitae	RCV001091093	SCV003295523	pathogenic	not provided	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser192Argfs*64) in the ACY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACY1 are known to be pathogenic (PMID: 16465618, 21414403, 24997716). This variant is present in population databases (rs770702363, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with aminoacylase 1 deficiency (PMID: 24997716, 31980526). ClinVar contains an entry for this variant (Variation ID: 800812). For these reasons, this variant has been classified as Pathogenic.
Lifecell International Pvt. Ltd	RCV000984988	SCV003923316	pathogenic	Aminoacylase 1 deficiency		criteria provided, single submitter	clinical testing	A Homozygote Frameshift variant c.574_575insG in Exon 8 of the ACY1 gene was identified. The variant is predicted to cause a frameshift and consequent premature termination of the protein (p.Ser192fs*64). The observed variant has a minor allele frequency of 0.00012% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant was found in ClinVar (Variant ID :800812) with a classification of Pathogenic and a review status of (2 star) criteria provided, multiple submitters, no conflicts. The variant has been previously reported in patients with ACY1D (Alessandrì MG et al.,2014). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
GeneDx	RCV001091093	SCV004014262	likely pathogenic	not provided	2023-03-31	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34426522, 31980526, 24367280, 29653693, 24997716, 35112591)
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000984988	SCV001132914	pathogenic	Aminoacylase 1 deficiency	2019-08-25	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000984988	SCV003927903	pathogenic	Aminoacylase 1 deficiency	2023-04-01	no assertion criteria provided	clinical testing