Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_020320.5(RARS2):c.110+5A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000421 in 1,426,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
RARS2 (HGNC:21406): (arginyl-tRNA synthetase 2, mitochondrial) This nuclear gene encodes a protein that localizes to the mitochondria, where it catalyzes the transfer of L-arginine to its cognate tRNA, an important step in translation of mitochondrially-encoded proteins. Defects in this gene are a cause of pontocerebellar hypoplasia type 6 (PCH6). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-87569512-T-C is Pathogenic according to our data. Variant chr6-87569512-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Oct 01, 2007
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only
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Jul 25, 2023
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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not provided Pathogenic:2
Jun 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Mar 07, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change falls in intron 2 of the RARS2 gene. It does not directly change the encoded amino acid sequence of the RARS2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs63749985, gnomAD 0.003%). This variant has been observed in individuals with pontocerebellar hypoplasia (PMID: 17847012, 26970947). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2+5A>G. ClinVar contains an entry for this variant (Variation ID: 891). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in exon 2 skipping and introduces a premature termination codon (PMID: 17847012). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -