rs207460005

Variant names:

• chrM-14780-AAATT-A
• rs207460005
• ENST00000361789.2:c.41_44delTTAA

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The ENST00000361789.2(MT-CYB):​c.41_44delTTAA​(p.Ile14ThrfsTer27) variant causes a frameshift change. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-CYB ENST00000361789.2 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 PD-/-MELAS
• Conservation: PhyloP100: 6.95
• Publications: 1 publications found

Genes affected

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ND6 (HGNC:7462): (mitochondrially encoded NADH dehydrogenase 6) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Predicted to be located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominante 2B. [provided by Alliance of Genome Resources, Apr 2022]

TRNE (HGNC:7479): (mitochondrially encoded tRNA glutamic acid)

TRNE Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• 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 VariationId is 9686.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTB	unassigned_transcript_4818	c.41_44delTTAA	p.Ile14fs	frameshift_variant	Exon 1 of 1
ND6	unassigned_transcript_4816	c.-111_-108delAATT		upstream_gene_variant
TRNE	unassigned_transcript_4817	c.-42_-39delAATT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CYB	ENST00000361789.2	c.41_44delTTAA	p.Ile14ThrfsTer27	frameshift_variant	Exon 1 of 1	6		ENSP00000354554.2
MT-ND6	ENST00000361681.2	c.-111_-108delAATT		upstream_gene_variant		6		ENSP00000354665.2
MT-TE	ENST00000387459.1	n.-42_-39delAATT		upstream_gene_variant		6

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Mitomap

Disease(s): PD-/-MELAS

Status: Cfrm-[LP]

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Parkinsonism/MELAS overlap syndrome Pathogenic:1

Jan 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Pathogenic:1

Dec 11, 2023

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

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.9

Other links and lift over

dbSNP: rs207460005; hg19: chrM-14781;