rs387906423

Variant names:

• chrM-8617-A-AT
• rs387906423
• ENST00000361899.2:c.92dupT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM6_Supporting PP1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.8618dupT (p.Thr33Hisfs*32) variant in MT-ATP6 has been reported in two unrelated individuals with primary mitochondrial disease (PS4_supporting; PMIDs: 32042910, 19124644). Clinical features in these individuals include developmental delay, learning difficulties, ataxia, spastic paraparesis, headache, cerebellar atrophy, white matter abnormalities, hearing loss, kidney failure, diabetes, cataracts, optic atrophy, retinal dystrophy, and short stature. The heteroplasmy levels in affected individuals ranged from 20% to 85%. This variant occurred de novo in one individual (absent in blood from mother, sister, and maternal aunt; PM6_supporting, PMID:19124644). This variant segregated with disease in the other family (proband with heteroplasmy levels ranging from 20-65%; unaffected individuals including mother, sister, and maternal aunt with lower heteroplasmy levels ranging from 0-24%; PP1; PMID:32042910). This frameshift variant results in a significant (>10%) truncation of the MT-ATP6 protein (PVS1_strong). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). There are no in silico predictors for this type of variant in mitochondrial DNA. 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 August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM6_supporting, PP1, PM2_supporting, PVS1_strong. LINK:https://erepo.genome.network/evrepo/ui/classification/CA254849/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 frameshift
• Clinical Significance: Likely pathogenic reviewed by expert panel P:2 NARP/cognitive-decline+abnormal-brain-MRI+impaired-kidney-function
• Conservation: PhyloP100: 0.809
• Publications: 1 publications found

Genes affected

MT-ATP6 (HGNC:7414): (mitochondrially encoded ATP synthase 6) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in Leber hereditary optic neuropathy; NARP syndrome; Parkinson's disease; multiple sclerosis; and systemic lupus erythematosus. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 (HGNC:7415): (mitochondrially encoded ATP synthase 8) Contributes to proton-transporting ATP synthase activity, rotational mechanism. Involved in mitochondrial ATP synthesis coupled proton transport. Part of mitochondrial proton-transporting ATP synthase complex. Implicated in multiple sclerosis and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

MT-ATP8 Gene-Disease associations (from GenCC):

• mitochondrial proton-transporting ATP synthase complex deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• periodic paralysis with later-onset distal motor neuropathy

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR, Mitochondrial Classification: LIMITED Submitted by: Illumina, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.92dupT	p.Thr33HisfsTer32	frameshift	Exon 1 of 1	ENSP00000354632.2	P00846
	MT-ATP8	ENST00000361851.1	TSL:6	c.*45_*46insT		downstream_gene	N/A	ENSP00000355265.1	P03928

Frequencies

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

Mitomap

Disease(s): NARP/cognitive-decline+abnormal-brain-MRI+impaired-kidney-function

Status: Reported

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial disease (1)
1	-	-	NARP syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.81

Other links and lift over

dbSNP: rs387906423; hg19: chrM-8618;