Submissions for variant NM_001114753.3(ENG):c.1309C>T (p.Arg437Trp)

gnomAD frequency: 0.00001  dbSNP: rs1434169817

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000756074	SCV000883789	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2019-06-01	criteria provided, single submitter	clinical testing	The ENG c.1309C>T; p.Arg437Trp variant (rs1434169817) is reported in the literature in individuals with symptoms of HHT (Bossler 2006, Gedge 2007), and has been identified by our laboratory in several unrelated individuals affected with HHT. Additionally, a different alteration at this codon (p.Arg437Gln) has also been identified by our laboratory in multiple affected individuals and is considered pathogenic. The p.Arg437Trp variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Based on available information, this variant is considered to be pathogenic. REFERENCES Bossler AD et al. Novel mutations in ENG and ACVRL1 identified in a series of 200 individuals undergoing clinical genetic testing for hereditary hemorrhagic telangiectasia (HHT): correlation of genotype with phenotype. Hum Mutat. 2006 Jul;27(7):667-75. Gedge F et al. Clinical and analytical sensitivities in hereditary hemorrhagic telangiectasia testing and a report of de novo mutations. J Mol Diagn. 2007 Apr;9(2):258-65.
Invitae	RCV001062873	SCV001227696	pathogenic	Hereditary hemorrhagic telangiectasia	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 437 of the ENG protein (p.Arg437Trp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of ENG-related conditions (PMID: 16752392, 20414677, 21158752, 23535011; Invitae). ClinVar contains an entry for this variant (Variation ID: 618082). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The tryptophan amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect ENG function (PMID: 22022569). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg437 amino acid residue in ENG. Other variant(s) that disrupt this residue have been observed in individuals with ENG-related conditions (PMID: 21158752, 24001356), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001726323	SCV001962573	likely pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002386313	SCV002694297	pathogenic	Cardiovascular phenotype	2021-07-16	criteria provided, single submitter	clinical testing	The p.R437W pathogenic mutation (also known as c.1309C>T), located in coding exon 10 of the ENG gene, results from a C to T substitution at nucleotide position 1309. The arginine at codon 437 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation was first described in an individual with epistaxis and telangiectasias (Bossler AD et al. Hum. Mutat., 2006 Jul;27:667-75). In addition, this mutation has been reported in several individuals with a clinical diagnosis of hereditary hemorrhagic telangiectasia (HHT) (Gedge F et al. J Mol Diagn, 2007 Apr;9:258-65; McDonald J et al. Clin Genet, 2011 Apr;79:335-44; Tørring PM et al. Clin. Genet., 2014 Aug;86:123-33; McDonald J et al. Genet Med, 2020 07;22:1201-1205). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000756074	SCV002767934	pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Hereditary Hemorrhagic Telangiectasia type 1 (MIM#187300). Loss-of-function variants have been reported, while missense variants have been demonstrated to have both loss of function and dominant negative effects on protein activity (PMID: 25312062). (I). 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0600 - Variant is located in the annotated Zona pellucida-like domain (NCBI). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as pathogenic in multiple patients with hereditary hemorrhagic telangiectasia type 1 (ClinVar, PMID: 17384219, 20414677) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001726323	SCV003761969	likely pathogenic	not provided	2023-01-27	criteria provided, single submitter	clinical testing	Protein harboring p.(R437W) is reported to traffic to the plasma membrane similarly to the wild-type protein, though no further functional assessment was reported (Ali et al., 2011); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16752392, 24001356, 23535011, 20414677, 22022569, 17384219, 32300199, 21158752)
Mayo Clinic Laboratories, Mayo Clinic	RCV001726323	SCV004226805	likely pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing	PP4, PM1, PM2_supporting, PS4_moderate
Molecular Genetics, Royal Melbourne Hospital	RCV001062873	SCV004812564	likely pathogenic	Hereditary hemorrhagic telangiectasia	2023-03-30	criteria provided, single submitter	clinical testing	This sequence change in ENG is predicted to replace arginine with tryptophan at codon 437, p.(Arg437Trp). The arginine residue is weakly conserved (35/45 vertebrates, UCSC), and is located in the zona pellucida domain. There is a large physicochemical difference between arginine and tryptophan. This variant is present in a single European (non-Finnish) individual in the population database gnomAD v3.1 (1/68,052 alleles). This variant has been reported in several probands/families with a clinical diagnosis of hereditary haemorrhagic telangiectasia (HHT; ClinVar; PMID: 17384219, 20414677, 23535011; ARUP ENG database; Royal Melbourne Hospital). The variant has been reported to segregate with HHT in at least one affected family member from a single family (PMID: 23535011). Multiple lines of computational evidence have conflicting predictions for the missense substitution (5/6 algorithms predict benign). Other missense variants in the same codon (p.Arg437) have been reported in individuals with HHT (PMID: 21158752, 24001356). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PS4_VeryStrong, PM2_Supporting.