Submissions for variant NM_001083614.2(EARS2):c.1A>G (p.Met1Val)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004783668	SCV005394761	pathogenic	Leukoencephalopathy-thalamus and brainstem anomalies-high lactate syndrome	2024-09-24	criteria provided, single submitter	clinical testing	Variant summary: EARS2 c.1A>G (p.Met1?, aka p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. The first potential downstream in-frame start codon (ATG) is located in exon 2 at Met94, which is not a canonical initiation codon in any known alternative transcripts. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.1A>G has been reported in the literature in multiple individuals affected with Leukoencephalopathy-Thalamus And Brainstem Anomalies-High Lactate Syndrome or related phenotypes (e.g. Steenweg_2012, Nogueira_2019, Roux_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22492562, 30831263, 33972171). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic.