Submissions for variant NM_005932.4(MIPEP):c.541C>T (p.Arg181Ter)

dbSNP: rs866158774

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001195538	SCV001365918	likely pathogenic	Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome	2020-02-11	criteria provided, single submitter	clinical testing	The p.Arg181X variant in MIPEP has not been previously reported in individuals with a severe cardiac and neurodevelopmental disease but has been identified in 3/115251 chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive carrier frequency. This variant was identified in compound heterozygous state with a variant of uncertain significance in an individual with childhood-onset heart failure, absent speech, and inability to walk by the Broad Institute Rare Genomes Project. This nonsense variant leads to a premature termination codon at position 181, which is predicted to lead to a truncated or absent protein. Loss of function of the MIPEP gene is associated to autosomal recessive neurodevelopmental disease with cardiomyopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive neurodevelopmental disease with cardiomyopathy. ACMG/AMP Criteria applied: PVS1, PM2.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001195538	SCV003761332	likely pathogenic	Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Arg181Ter variant in MIPEP was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 930152), in one individual with childhood-onset heart failure, absent speech, and inability to walk (Broad Institute Rare Genomes Project). The p.Arg181Ter variant in MIPEP has not been previously reported in individuals with combined oxidative phosphorylation deficiency 31. This variant has been identified in 0.006% (1/16940) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs866158774). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 930107) and has been interpreted as likely pathogenic by the Mass General Brigham Laboratory for Personalized Medicine. This nonsense variant leads to a premature termination codon at position 181, which is predicted to lead to a truncated or absent protein. Loss of function of the MIPEP gene is strongly associated to combined oxidative phosphorylation deficiency 31. In summary, although there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PVS1, PM2_supporting (Richards 2015).