Submissions for variant NM_001611.5(ACP5):c.325G>A (p.Gly109Arg)

gnomAD frequency: 0.00003  dbSNP: rs781050795

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000624296	SCV000742527	pathogenic	Inborn genetic diseases	2017-05-15	criteria provided, single submitter	clinical testing
Invitae	RCV000022709	SCV001576510	pathogenic	Spondyloenchondrodysplasia with immune dysregulation	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 109 of the ACP5 protein (p.Gly109Arg). This variant is present in population databases (rs781050795, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of spondyloenchondrodysplasia with immune dysregulation (PMID: 21217752, 26951490; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 29833). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACP5 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000022709	SCV002572865	likely pathogenic	Spondyloenchondrodysplasia with immune dysregulation	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029833). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21217752). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000022709	SCV003806980	pathogenic	Spondyloenchondrodysplasia with immune dysregulation	2022-08-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP3 supporting
PreventionGenetics, part of Exact Sciences	RCV003421931	SCV004117000	pathogenic	ACP5-related condition	2023-01-17	criteria provided, single submitter	clinical testing	The ACP5 c.325G>A variant is predicted to result in the amino acid substitution p.Gly109Arg. This variant has been reported along with another variant in ACP5 or in the homozygous state in individuals with spondyloenchondrodysplasia (SPENCD) (Lausch et al. 2011. PubMed ID: 21217752; Briggs et al. 2016. PubMed ID: 26951490). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11687595-C-T) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/29833/). This variant is interpreted as pathogenic.
OMIM	RCV000022709	SCV000043998	pathogenic	Spondyloenchondrodysplasia with immune dysregulation	2011-02-01	no assertion criteria provided	literature only