Submissions for variant NM_000789.4(ACE):c.47_70del (p.Leu16_Pro23del)

dbSNP: rs983649759

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001594282	SCV001826552	pathogenic	not provided	2021-01-15	criteria provided, single submitter	clinical testing	In-frame deletion of 8 amino acids in a non-repeat region predicted to critically alter the protein; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22095942)
Fulgent Genetics, Fulgent Genetics	RCV002495957	SCV002794876	likely pathogenic	Microvascular complications of diabetes, susceptibility to, 3; Hemorrhage, intracerebral, susceptibility to; Renal tubular dysgenesis of genetic origin	2021-12-03	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003336423	SCV004046317	pathogenic	Renal tubular dysgenesis		criteria provided, single submitter	clinical testing	This 24 base pair in-frame deletion variant found in exon 1 of 25 leads to the loss of 8 amino acid residues. This variant has been previously reported in the homozygous state in two individuals and the compound heterozygous state with a pathogenic truncating variant in one individual with Renal Tubular Dysgenesis (PMID: 22095942). These individuals exhibited high renin expression, indicating a loss of ACE protein function. Variants in exon 1 of the ACE gene that completely disrupt the signal peptide sequence or result in the deletion of one or several leucine residues are predicted to prevent the normal translocation of the protein to the endoplasmic reticulum (PMID: 22095942, 19664745). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0096% (9/93296) and thus is presumed to be rare. Based on the available evidence, the c.47_70del (p.Leu16_Pro23del) variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001594282	SCV004318116	uncertain significance	not provided	2024-06-20	criteria provided, single submitter	clinical testing	This variant, c.47_70del, results in the deletion of 8 amino acid(s) of the ACE protein (p.Leu16_Pro23del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (no rsID available, gnomAD 0.04%). This variant has been observed in individuals with renal tubular dysgenesis (PMID: 22095942, 35848000). ClinVar contains an entry for this variant (Variation ID: 1219086). 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.
PreventionGenetics, part of Exact Sciences	RCV004738354	SCV005362931	pathogenic	ACE-related disorder	2024-08-06	no assertion criteria provided	clinical testing	The ACE c.47_70del24 variant is predicted to result in an in-frame deletion (p.Leu16_Pro23del). This variant has been reported in the homozygous and compound heterozygous state in multiple individuals with autosomal recessive renal tubular dysgenesis (Table 2, Gribouval et al. 2012. PubMed ID: 22095942; Gaffar et al. 2022. PubMed ID: 35848000). Deletions of one or multiple leucine residues in exon 1 of the ACE gene have been commonly reported to be pathogenic for autosomal recessive renal tubular dysgenesis secondary to disrupted translocation of the protein to the endoplasmic reticulum (Gribouval et al. 2010. PubMed ID: 20607303). This variant is reported in 0.018% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as likely pathogenic/pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1219086/). In summary, we classify this variant as pathogenic.