Submissions for variant NM_001114753.3(ENG):c.1316A>C (p.Lys439Thr)

gnomAD frequency: 0.00005  dbSNP: rs368533266

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen	RCV000315391	SCV004805879	likely benign	Telangiectasia, hereditary hemorrhagic, type 1	2024-03-15	reviewed by expert panel	curation	The NM_001114753.3: c.1316A>C variant in ENG is a missense variant predicted to cause substitution of lysine by threonine at amino acid 439 (p.Lys439Thr). The filtering allele frequency (the lower threshold of the 95% CI of 15/10368) of the c.1316A>C variant in ENG is 0.0008918 for Ashkenazi Jewish chromosomes by gnomAD v2.1.1, which is higher than the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel threshold (>0.0008-0.002) for BS1_Supporting, and therefore meets this criterion (BS1_Supporting). The computational predictor REVEL gives a score of 0.041, which is below the threshold of less than or equal to 0.15, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on ENG function (BP4). Additionally, functional assays showed the variant protein localized to the cell surface and had normal BMP9 response indicating that this variant does not impact protein function (BS3_Supporting; PMID: 25312062). In summary, this variant meets the criteria to be classified as likely benign 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: BS1_Supporting, BP4, BS3_Supporting (specification version 1.0.0; 1/4/2024).
Illumina Laboratory Services, Illumina	RCV000315391	SCV000477327	uncertain significance	Telangiectasia, hereditary hemorrhagic, type 1	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201388	SCV000546114	benign	Hereditary hemorrhagic telangiectasia	2024-01-18	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757218	SCV000885364	uncertain significance	not provided	2017-09-14	criteria provided, single submitter	clinical testing	The c.1316A>C; p.Lys439Thr variant (rs368533266) was reported in a patient that carried a deletion in exon 6 of the ENG gene (Mallet, 2015). Functional studies by Mallet (2015) also showed that the p.Lys439Thr is properly targeted to the cell surface and stimulates ALK1 signaling in response to BMP9, features that are otherwise reduced in defective ENG polypeptides. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.15 percent in the Ashkenazi Jewish population (identified on 15 out of 9,850 chromosomes), and is reported to the ClinVar database (Variation ID: 365088). The lysine at position 439 is moderately conserved considering 12 species (Alamut v2.9.0) and computational analyses of the p.Lys439Thr variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Based on these observations, the p.Lys439Thr variant is likely to be benign.