Submissions for variant NM_018116.4(MSTO1):c.836G>A (p.Arg279His)

gnomAD frequency: 0.00008  dbSNP: rs563943670

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000768553	SCV001430735	uncertain significance	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	2020-05-28	criteria provided, single submitter	research	The heterozygous p.Arg279His variant in MSTO1 was identified by our study, in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with myopathy, mitochondrial, and ataxia (PMID: 31463572). The p.Arg279His variant in MSTO1 has been reported in 8 additional individuals with myopathy, mitochondrial, and ataxia, segregated with disease in 5 affected relatives from 2 families (PMID: 30684668, 31463572). The presence of this variant in combination with a reported pathogenic/likely pathogenic variant and in 2 individuals with myopathy, mitochondrial, and ataxia increases the likelihood that the p.Arg279His variant is pathogenic (VariationID: 504109; PMID: 30684668, 31463572). It has been identified in 0.02% (6/35260) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs563943670). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. In vitro functional studies provide some evidence that the p.Arg279His variant may impact protein function (PMID: 31463572). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP1, PS3, PM3, BP4 (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV001816791	SCV002064341	likely pathogenic	not provided	2020-08-10	criteria provided, single submitter	clinical testing	The sequence change, c.836G>A in exon 9, results in an amino acid change, p.Arg279His. This sequence change has been described in the gnomAD database with a low population frequency of 0.007796% (dbSNP rs563943670). The p.Arg279His change affects a moderately conserved amino acid residue located in a domain of the MSTO1 protein that is known to be functional. This particular sequence change has been reported in the compound heterozygous state with a loss of function variant in two unrelated individuals with cerebellar atrophy, intellectual disability and pigmentary retinopathy (PMIDL 29339779). This sequence change was also reported to segregate in the compound heterozygous state in one family with muscle weakness, motor delay, dysarthria, learning difficulty, and cerebellar atrophy (PMID: 31463572). Muscle biopsy findings were consistent with a dystrophic process (PMID: 31463572). Functional studies using patient derived fibroblasts demonstrated a significant reduction in MSTO1 protein and fragmented mitochondrial networks (PMID: 31463572). Lastly, another amino acid change at this position (c.835C>T p.Arg279Cys) was reported in one individual with muscle weakness, dysarthria, and learning difficulties (PMID: 31463572). Collectively, these evidences indicate that the c.836G>A sequence change is likely pathogenic.
GeneDx	RCV001816791	SCV002099750	pathogenic	not provided	2023-06-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29339779, 31463572, 30684668, 33163565)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001816791	SCV003459822	pathogenic	not provided	2022-09-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSTO1 protein function. ClinVar contains an entry for this variant (Variation ID: 590277). This missense change has been observed in individual(s) with mitochondrial myopathy and ataxia (PMID: 29339779, 30684668). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs563943670, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 279 of the MSTO1 protein (p.Arg279His).
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology	RCV000768553	SCV000852006	uncertain significance	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome		no assertion criteria provided	clinical testing
OMIM	RCV000768553	SCV001448688	pathogenic	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	2022-11-30	no assertion criteria provided	literature only