ClinVar Miner

Submissions for variant NM_000118.3(ENG):c.-9G>A (rs368423516)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085762 SCV000557845 likely benign Hereditary hemorrhagic telangiectasia 2020-09-19 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000460114 SCV001155740 likely benign not provided 2017-04-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000139 SCV001156619 pathogenic Hereditary hemorrhagic telangiectasia type 1 2018-12-31 criteria provided, single submitter clinical testing The ENG c.-9G>A variant (rs368423516 ) has been described in the literature in families with hereditary hemorrhagic telangiectasia or pulmonary arterial hypertension and has been implicated as a hypomorphic allele, causing reduced functionality (Best 2017, Kim 2011, McDonald 2011). Additionally, this variant has been shown to cause reduced translation (Damjanovich 2011). The variant is listed in the ClinVar database (Variation ID: 414302) and in the general population with an allele frequency of 0.05% (108/222760 alleles) in the Genome Aggregation Database. The nucleotide at the -9 position is moderately conserved across mammals and creates a novel methionine translational start and the inclusion of additional new amino acids. Due to this variant being described in the literature as a hypomorphic allele and shown to reduced translation, we consider this variant is pathogenic with mild clinical outcomes. References: Best DH et al. EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension. Chest. 2017 Apr;151(4):821-828 Damjanovich K et al. 5'UTR mutations of ENG cause hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2011 Dec 22;6:85. Kim MJ et al. Clinical and genetic analyses of three Korean families with hereditary hemorrhagic telangiectasia. BMC Med Genet. 2011 Oct 3;12:130. McDonald J et al. Molecular diagnosis in hereditary hemorrhagic telangiectasia: findings in a series tested simultaneously by sequencing and deletion/duplication analysis. Clin Genet. 2011 Apr;79(4):335-44.
Illumina Clinical Services Laboratory,Illumina RCV001000139 SCV001332252 uncertain significance Hereditary hemorrhagic telangiectasia type 1 2018-04-23 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Clinical Genetics,Academic Medical Center RCV000460114 SCV001922505 likely benign not provided no assertion criteria provided clinical testing

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