M-14780-AAATT-A

Position:

• chrM-14780-AAATT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: CYTB frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 PD-/-MELAS
• Conservation: PhyloP100: 6.95

Genes affected

CYTB (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-14780-AAATT-A is Pathogenic according to our data. Variant chrM-14780-AAATT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9686.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYTB	unassigned_transcript_4819	c.41_44delTTAA	p.Ile14fs	frameshift_variant	1/1
TRNE	unassigned_transcript_4818	c.-42_-39delAATT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt

Frequencies

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap

PD-/-MELAS

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Parkinsonism/MELAS overlap syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1999

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen

Dec 11, 2023

The m.14787_14790delTTAA (p.Ile14ThrfsTer27) variant in MT-CYB has been reported in one individual to date, in a man with features consistent with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and akinetic rigid syndrome. Clinical features included fine motor incoordination, concentration difficulty, fatigue, periods with regressive behavior, Wolff-Parkinson-White arrhythmia, mild left ventricular hypertrophy, seizures, and cortical blindness. He walked with a flexed body posture, reduced arm swing, mild shuffling gait, had resting tremor of the hands, and increased muscle tone. Brain MRI showed diffuse atrophy and lesions consistent with cerebral infarcts in the left and right parietooccipital region. Blood and cerebrospinal fluid lactate levels were elevated. Muscle biopsy electron microscopy showed aggregates of subsarcolemmal mitochondria. He had an isolated complex III deficiency in muscle (14% lowest normal value). The variant was present at 60% heteroplasmy in blood, 60% in hair, 60% in buccal, 60% in fibroblasts, and 95% muscle (PMID: 9894888). As this is the only case reported to date, PS4 could not be applied. The variant was absent in blood, buccal, and hair samples from his healthy mother (PM6_supporting). Computational predictors are not applicable for this variant type precluding consideration for PP3 or BP4. This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). This variant results in a frame shift from codon 13 onward and is predicted to result in a nonsense stretch of amino acids terminating at an early stop at codon 50 (PVS1_strong). There are no cybrids, single fiber studies, or other functional assays reported on this variant. In summary, this variant meets criteria to be classified as likely pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on December 11, 2023. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PM6_supporting, PM2_supporting, PVS1_strong. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs207460005; hg19: chrM-14781;