Submissions for variant NM_016034.5(MRPS2):c.300-2A>G

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	RCV003123499	SCV003801121	likely pathogenic	Combined oxidative phosphorylation deficiency 36	2023-01-22	criteria provided, single submitter	clinical testing	Variant summary: MRPS2 c.300-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 3' splicing acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 247078 control chromosomes. To our knowledge, no occurrence of c.300-2A>G in individuals affected with Combined Oxidative Phosphorylation Deficiency 36 and no experimental evidence demonstrating its impact on protein function have been reported. To our knowledge, only bi-allelically inherited missense variants in the MRPS2 gene have been reported among individuals affected with features of sensorineural hearing impairment, mild developmental delay, hypoglycemia, and a combined OXPHOS deficiency (Gardeitchik_2018). However, a decrease in the steady-state amounts of mutant MRPS2 in patient derived fibroblasts, an inhibition of mitochondrial translation and resultant combined OXPHOS deficiency that was restored by re-introduction of wild-type MRPS2 supports a loss of function mechanism of disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.