Submissions for variant NM_001114753.3(ENG):c.1312A>T (p.Lys438Ter)

dbSNP: rs863223536

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198335	SCV000250083	pathogenic	not provided	2017-08-21	criteria provided, single submitter	clinical testing	The K438X variant in the ENG gene has not been reported as a pathogenic or benign to our knowledge and it is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the ENG gene have been reported in Human Gene Mutation Database in association with HHT (Stenson et al., 2014).In summary, K438X in the ENG gene is interpreted as a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001056962	SCV001221429	pathogenic	Hereditary hemorrhagic telangiectasia	2023-06-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys438*) in the ENG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENG are known to be pathogenic (PMID: 15879500). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ENG-related conditions. ClinVar contains an entry for this variant (Variation ID: 213210).
Ambry Genetics	RCV002381667	SCV002694439	pathogenic	Cardiovascular phenotype	2023-03-03	criteria provided, single submitter	clinical testing	The p.K438* pathogenic mutation (also known as c.1312A>T), located in coding exon 11 of the ENG gene, results from an A to T substitution at nucleotide position 1312. This changes the amino acid from a lysine to a stop codon within coding exon 11. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Neuberg Centre For Genomic Medicine, NCGM	RCV005089996	SCV005849041	likely pathogenic	Telangiectasia, hereditary hemorrhagic, type 1	2023-06-22	criteria provided, single submitter	clinical testing	The stop gained c.1312A>T(p.Lys438Ter) variant in ENG gene has been submitted to the ClinVar database as Pathogenic. This variant has not been reported in the literature in individuals, to our knowledge. The c.1312A>T variant is absent in gnomAD Exomes. Computational evidence (MutationTaster -Disease causing) predicts damaging effect on protein structure and function for this variant. The nucleotide change c.1312A>T in ENG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing (Suzuki A, et. al., 2012). Additional functional studies are required to prove pathogenicity of the variant. For these reasons, this variant has been classified as Likely Pathogenic.