Submissions for variant NM_020191.4(MRPS22):c.1032_1035dup (p.Leu346fs)

gnomAD frequency: 0.00007  dbSNP: rs772578397

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778679	SCV000915020	uncertain significance	Hypotonia with lactic acidemia and hyperammonemia	2018-11-14	criteria provided, single submitter	clinical testing	The MRPS22 c.1032_1035dupAACA (p.Leu346AsnfsTer21) variant results in a frameshift and is predicted to cause an elongation of the protein. It was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018) and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score for this variant, it could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene and cDNA change, and amino acid change. No publications were found based on this search. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for this combined oxidative phosphorylation deficiency.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000778679	SCV001367797	pathogenic	Hypotonia with lactic acidemia and hyperammonemia	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PS1. This variant was detected in homozygous state.
GeneDx	RCV001556234	SCV001777776	likely pathogenic	not provided	2023-06-23	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to result in protein elongation, as the last 15 amino acids are lost and replaced with 20 incorrect amino acids; This variant is associated with the following publications: (PMID: 33917098, 25663021, 31683770, 34426522, 33314036)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001556234	SCV002293901	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the MRPS22 gene (p.Leu346Asnfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the MRPS22 protein and extend the protein by 5 additional amino acid residues. This variant is present in population databases (rs772578397, gnomAD 0.02%). This frameshift has been observed in individuals with combined oxidative phosphorylation deficiency (PMID: 25663021, 31683770). ClinVar contains an entry for this variant (Variation ID: 631909). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.