Submissions for variant NM_018116.4(MSTO1):c.706G>C (p.Asp236His)

gnomAD frequency: 0.00013  dbSNP: rs753488873

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001254689	SCV001430752	likely pathogenic	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	2020-05-28	criteria provided, single submitter	research	The heterozygous p.Asp236His variant in MSTO1 was identified by our study, in the compound heterozygous state, along with another variant of uncertain significance, in unrelated 2 individuals with myopathy, mitochondrial, and ataxia. In total, including the previously mentioned probands, this variant has been identified in 4 unrelated probands as well as 2 affected relatives (PMID: 31463572). The presence of this variant in trans with reported variants of uncertain significance in affected individuals increases the likelihood that the p.Asp236His variant is pathogenic (PMID: 31463572). The variant p.Asp236His variant been identified in 0.01% (17/128336) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs753488873). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that the p.Asp236His variant may impact protein function (PMID: 31463572). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_moderate, PM3, PM2_supporting, PP1 (Richards 2015).
Revvity Omics, Revvity	RCV001254689	SCV002023531	likely pathogenic	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	2022-07-08	criteria provided, single submitter	clinical testing
GeneDx	RCV001786458	SCV002028990	pathogenic	not provided	2022-09-28	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: 31463572, 33163565, 34426522)
Invitae	RCV001786458	SCV003494724	pathogenic	not provided	2023-06-06	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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSTO1 protein function. ClinVar contains an entry for this variant (Variation ID: 977147). This missense change has been observed in individual(s) with MSTO1-related conditions (PMID: 31463572). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs753488873, gnomAD 0.02%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 236 of the MSTO1 protein (p.Asp236His).
OMIM	RCV001254689	SCV002600212	pathogenic	Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome	2022-11-10	no assertion criteria provided	literature only