ClinVar Genomic variation as it relates to human health

Variant summary: EMC1 (KIAA0090) c.245C>T (p.Thr82Met) results in a non-conservative amino acid change located in the Pyrrolo-quinoline quinone repeat (IPR002372) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251362 control chromosomes (gnomAD). c.245C>T has been reported in the literature in at least 4 homozygous individuals affected with Cerebellar Atrophy, Visual Impairment, And Psychomotor Retardation (Harel_2016, Baker_2019). Three of these individuals were part of the same family where the variant was found to co-segregate with disease (Harel_2016). These data indicate that the variant is likely to be associated with disease. A functional study demonstrated the variant was not able to restore sox10 expression and tadpole movement in emc1-depleted Xenopus embryos (authors assayed the expression of sox10 as a marker of effects on neural crest cells and tadpole motility as a marker of broader neurodevelopmental function) (Marquez_2020). Another study reported the variant to result in depletion of the N-cytoplasmic polytopic client (TMEM97) (Miller-Vedam_2020). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic and two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

A Heterozygous Missense variant c.245C>T in Exon 3 of the EMC1 gene that results in the amino acid substitution p.Thr82Met was identified. The observed variant has a minor allele frequency of 0.00002% in gnomAD exomes. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as conflictingInterpretations of Pathogenicity(Variant ID 219100).This variant has been previously reported in Baker et al., 2019. Based on the above evidence this variant has been classified as Likely Pathogenic according to the ACMG guidelines.

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the EMC1 protein (p.Thr82Met). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive EMC1-related disorders (PMID: 26942288; external communication). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 219100). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.

Published functional studies demonstrate p.(T82M) mRNA did not significantly restore SOX10 expression, a measure of EMC1 function, and significantly reduced motility in a Xenopus model (PMID: 31904590); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29271071, 26942288, 34426522, 35234901, 32092440, Peer-Zada2021[casereport], 30826214, 37098815, 33236988, 30577886, 31904590)

Variant interpretted as Likely pathogenic and reported on 06/18/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.