ClinVar Miner

Submissions for variant NM_000789.4(ACE):c.1522C>T (p.Arg508Ter)

gnomAD frequency: 0.00004  dbSNP: rs367797185
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics RCV000224863 SCV000280827 pathogenic not provided 2015-12-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000399495 SCV000404660 uncertain significance Renal tubular dysgenesis 2017-04-27 criteria provided, single submitter clinical testing The ACE c.1522C>T (p.Arg508Ter) stop-gained variant has been reported in one study in a severely affected neonatal individual in a compound heterozygous state along with a pathogenic truncating variant (Gribouval et al. 2012). The authors demonstrated that the individual carrying the p.Arg508Ter variant had very high renin expression which indicates a loss of ACE protein function. Control data are unavailable for this variant which is reported at a frequency of 0.000003 in the total population of the Exome Aggregation Consortium. Due to the potential impact of stop-gained variants and evidence from the literature, the p.Arg508Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for renal tubular dysgenesis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000399495 SCV004046318 pathogenic Renal tubular dysgenesis criteria provided, single submitter clinical testing This nonsense variant found in exon 10 of 25 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in a compound heterozygous state along with a pathogenic truncating variant in one individual with Renal Tubular Dysgenesis (PMID: 22095942). This individual exhibited high renin expression, indicating a loss of ACE protein function. It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0032% (9/282862) and thus is presumed to be rare. Based on the available evidence, the c.1522C>T (p.Arg508Ter) variant is classified as Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV000224863 SCV004297501 pathogenic not provided 2023-11-12 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg508*) in the ACE gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ACE are known to be pathogenic (PMID: 22095942). This variant is present in population databases (rs367797185, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with renal tubular dysgenesis (PMID: 22095942). ClinVar contains an entry for this variant (Variation ID: 235336). 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.
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin RCV004767179 SCV005380251 pathogenic Renal tubular dysgenesis of genetic origin criteria provided, single submitter not provided

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