rs200613617
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PS1_ModerateBP4BS2
The ENST00000362079.2(MT-CO3):c.598G>A(p.Ala200Thr) variant causes a missense change. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A200P) has been classified as Uncertain significance.
Frequency
Mitomap GenBank:
𝑓 0.0030 ( AC: 181 )
Consequence
MT-CO3
ENST00000362079.2 missense
ENST00000362079.2 missense
Scores
Apogee2
Uncertain
Clinical Significance
LHON-/-MS
Conservation
PhyloP100: 4.01
Genes affected
MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PS1
Transcript ENST00000362079.2 (MT-CO3) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
BP4
Apogee2 supports a benign effect, 0.3962503 < 0.5 .
BS2
High AC in GnomadMitoHomoplasmic at 205
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| COX3 | COX3.1 use as main transcript | c.598G>A | p.Ala200Thr | missense_variant | 1/1 | YP_003024032.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MT-CO3 | ENST00000362079.2 | c.598G>A | p.Ala200Thr | missense_variant | 1/1 | ENSP00000354982 | P1 |
Frequencies
GnomAD4 exome Cov.: 0
GnomAD4 exome
Cov.:
0
We have no GnomAD4 genomes data on this position. Probably position not covered by the project.
Mitomap GenBank
AF:
AC:
181
Gnomad homoplasmic
AF:
AC:
205
AN:
56420
Gnomad heteroplasmic
AF:
AC:
15
AN:
56420
Alfa
AF:
Hom.:
Mitomap
LHON-/-MS
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2Benign:2Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Leber optic atrophy Pathogenic:2Other:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 29, 1993 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
See cases Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PS1,PP3. This variant was detected in mitochondrial heteroplasmy state. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 21, 2017 | The m.9804G>A variant (rs200613617) has been reported as a primary pathogenic variant involved in Leber's hereditary optic neuropathy (LOHN; Johns 1993, Dogulu 2001, Savontaus 1995), and as a secondary variant (Matsumoto 1999). Initial studies identified the variant in 4 independent families, while noting its absence from healthy controls (Johns 1993, Dogulu 2001). However, in one family, the m.9804G>A variant was present in 3 asymptomatic family members (Dogulu 2001). This variant has also been previously observed by our laboratory in two patients, one with optic atrophy and one with chronic myoclonic disorder, neither of whom carried other significant variant in the mitochondrial genome or in 108 nuclear-encoded genes with mitochondrial function. This variant is listed in Mitomap with an overall frequency of 0.28%, and is found in the H6c haplogroup with a frequency of 95%. No functional studies have been conducted to determine the impact of the m.9804G>A variant on complex IV function. While it is possible that m.9804G>A is the primary pathogenic variant in this patient, the frequency in the H6c haplogroup suggests that it is unlikely to be pathogenic; however, due to conflicting evidence in the literature, we cannot classify this variant with certainty. - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 13, 2023 | The m.9804G>A variant in MT-CO3 is classified as benign because it has been identified in 0.5% (128/25840) of homoplasmic European alleles by gnomAD (http://gnomad.broadinstitute.org). In addition it was found at 95% frequency in the H6c haplogroup. ACMG/AMP Criteria applied: BA1. - |
Leigh syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine | Oct 17, 2019 | The NC_012920.1:m.9804G>A (YP_003024032.1:p.Ala200Thr) variant in MTCO3 gene is interpretated to be a Benign variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: BS1, BS2, BP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Apogee2
Uncertain
Hmtvar
Benign
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
DEOGEN2
Benign
T
LIST_S2
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
A
PROVEAN
Uncertain
D
Sift
Benign
D
Sift4G
Uncertain
D
GERP RS
Varity_R
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at