Submissions for variant NM_001114753.3(ENG):c.1645T>G (p.Cys549Gly)

dbSNP: rs1830376644

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV001289855	SCV005326486	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2024-09-11	reviewed by expert panel	curation	The NM_001114753.3: c.1645T>G variant in ENG is a missense variant predicted to cause substitution of cysteine by glycine at amino acid 549 (p.Cys549Gly). This variant has been reported in 3 probands with a phenotype consistent with Hereditary Hemorrhagic Telangiectasia (PS4_Moderate, Internal lab contributors, Invitae, Victorian Clinical Genetics Service). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861 which is above the threshold of 0.644, evidence that correlates with impact to ENG function (PP3). Another missense variant c.1646G>A, p.Cys549Tyr (PMIDs: 38828001, 20414677, 21158752; ClinVar Variation ID: 407135) in the same codon has been classified as pathogenic for Hereditary Hemorrhagic Telangiectasia by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PM5). This variant resides within a region, amino acid C549, of ENG that is defined as a mutational hotspot or critical functional domain by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel (PMIDs: 28564608, 25312062) (PM1). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PS4_Moderate, PM2_Supporting, PP3, PM5, PM1 (specifications version 1.1.0; 09/11/2024).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001289855	SCV001477854	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2019-10-21	criteria provided, single submitter	clinical testing	The ENG c.1645T>G; p.Cys549Gly variant, to our knowledge, is not reported in the medical literature or gene specific databases. This variant is also absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 549 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two different variants at this codon (Cys549Arg, Cys549Tyr) have been identified by our laboratory in multiple individuals affected with HHT and are considered to be pathogenic, giving further support of the importance of this residue. Based on available information, the p.Cys549Gly variant is considered to be likely pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001289855	SCV002768783	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2024-09-19	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with type 1 hereditary haemorrhagic telangiectasia (MIM#187300). Pathogenic missense variants have been demonstrated to have dominant negative and loss of function effects while premature termination variants are associated with a loss of function mechanism (PMIDs: 2508034, 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 cysteine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Zona pellucida domain and is part of a disulphide bond (DECIPHER, PMID: 22347366). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Two alternative changes, p.(Cys549Ser) and p.(Cys549Tyr), have been identified in more than four individuals with ENG-related features (ClinVar, PMIDs: 20414677, 21158752, 35346192). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported as likely pathogenic in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV003759041	SCV004462047	pathogenic	Hereditary hemorrhagic telangiectasia	2023-05-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys549 amino acid residue in ENG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20414677, 21158752; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt ENG protein function. ClinVar contains an entry for this variant (Variation ID: 995686). This missense change has been observed in individual(s) with hereditary hemorrhagic telangiectasia (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 549 of the ENG protein (p.Cys549Gly).