Submissions for variant NM_001114753.3(ENG):c.694C>T (p.Arg232Trp)

gnomAD frequency: 0.00014  dbSNP: rs200372420

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808290	SCV000948392	likely benign	Hereditary hemorrhagic telangiectasia	2024-05-16	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001001189	SCV001158345	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2019-03-28	criteria provided, single submitter	clinical testing	The ENG c.694C>T; p.Arg232Trp variant (rs200372420) is reported in the literature in an individual affected with intracranial aneurysm but also in several healthy controls (Santiago-Sim 2009). This variant is found in the African population with an overall allele frequency of 0.06% (15/24588 alleles) in the Genome Aggregation Database. The arginine at codon 232 is weakly conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Arg232Trp variant is uncertain at this time. References: Santiago-Sim T et al. Sequencing of TGF-beta pathway genes in familial cases of intracranial aneurysm. Stroke. 2009 May;40(5):1604-11.
Johns Hopkins Genomics, Johns Hopkins University	RCV001001189	SCV001548511	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2021-03-23	criteria provided, single submitter	clinical testing	ENG c.694C>T has been previously reported in an individual with an intracranial aneurysm, but also in three apparently healthy individuals. This ENG variant (rs200372420) is rare (<0.1%) in a large population dataset (gnomAD: 22/279074 total alleles; 0.008%; no homozygotes) and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be damaging. The arginine residue at this position is evolutionarily conserved across most of the mammals assessed, however a tryptophan is present at this position in two mammalian species. We consider the clinical significance of ENG c.694C>T to be uncertain at this time.
Ambry Genetics	RCV002363083	SCV002664359	likely benign	Cardiovascular phenotype	2021-12-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
PreventionGenetics, part of Exact Sciences	RCV004753049	SCV005350367	uncertain significance	ENG-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The ENG c.694C>T variant is predicted to result in the amino acid substitution p.Arg232Trp. This variant has been reported in an individual with an intracranial aneurysm (Santiago-Sim T et al 2009. PubMed ID: 19299629). This variant is reported in 0.061% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/652688/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.