Submissions for variant NM_000789.4(ACE):c.2299G>A (p.Glu767Lys)

gnomAD frequency: 0.00019  dbSNP: rs148995315

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000376190	SCV000404671	uncertain significance	Renal tubular dysgenesis	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Fulgent Genetics, Fulgent Genetics	RCV002487423	SCV002793747	likely benign	Microvascular complications of diabetes, susceptibility to, 3; Hemorrhage, intracerebral, susceptibility to; Renal tubular dysgenesis of genetic origin	2024-05-03	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001355158	SCV003271441	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 767 of the ACE protein (p.Glu767Lys). This variant is present in population databases (rs148995315, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ACE-related conditions. ClinVar contains an entry for this variant (Variation ID: 324391). 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 not expected to disrupt ACE protein function with a negative predictive value of 80%. 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355158	SCV001549953	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ACE p.Glu193Lys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs148995315), ClinVar (classified as a VUS by Illumina) and LOVD 3.0. The variant was also identified in control databases in 72 of 281502 chromosomes at a frequency of 0.000256 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 55 of 128060 chromosomes (freq: 0.00043), Other in 2 of 7214 chromosomes (freq: 0.000277), South Asian in 7 of 30614 chromosomes (freq: 0.000229), Latino in 6 of 35414 chromosomes (freq: 0.000169), African in 1 of 24896 chromosomes (freq: 0.00004) and European (Finnish) in 1 of 25046 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish and East Asian populations. The p.Glu193 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.