rs199476136

chrM-8851-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3 PP5_Strong

The ENST00000361899.2(MT-ATP6):c.325T>C(p.Trp109Arg) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.87
• Clinical Significance: Uncertain significance reviewed by expert panel P:5 U:2 O:1 BSN-/-Leigh-syndrome
• Conservation: PhyloP100: 5.98

Genes affected

ATP6 (HGNC:):

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP3: Apogee2 supports a deletorius effect, 0.8674359 >= 0.5 .
• PP5: Variant M-8851-T-C is Pathogenic according to our data. Variant chrM-8851-T-C is described in ClinVar as [Uncertain_significance]. Clinvar id is 9645.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, not_provided=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP6	ATP6.1	c.325T>C	p.Trp109Arg	missense_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-ATP6	ENST00000361899.2	c.325T>C	p.Trp109Arg	missense_variant	1/1			P1

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.000035 AC: 2 AN: 56428

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56428

Alfa AF: 0.000228 Hom.: 1

Mitomap

BSN-/-Leigh-syndrome

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5 Uncertain:2 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Leigh syndrome Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 19, 2021	This variant was identified as homoplasmic -
Likely pathogenic, 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.8851T>C (YP_003024031.1:p.Trp109Arg) variant in MTATP6 gene is interpretated to be a Likely Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PM9, PM10, PP3, PP4, PP6 -

Leber optic atrophy Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Apr 21, 2023	- -

Striatonigral degeneration, infantile, mitochondrial Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Mitochondrial disease Uncertain:1

Uncertain significance, reviewed by expert panel

curation

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

Mar 24, 2022

The m.8851T>C (p.W109R) variant in MT-ATP6 has been reported in 4 individuals with features of primary mitochondrial disease from 3 families. Affected individuals had variable ages of onset (first months of life to 3 years old, one with onset in early 20s, one with onset in 50s). Several affected individuals had a period of normal development followed by delay and regression. Progressive neuromuscular involvement in later onset forms has also been seen. Features include developmental delay, microcephaly, choreoathetotic movements, ataxia, axonal neuropathy, progressive cognitive impairment, retinal dystrophy, hearing loss, and increase of subsarcolemmal mitochondria in muscle. Brain MRI showed bilateral basal ganglia lesions, Leigh syndrome, and cerebellar atrophy; and lab abnormalities included elevated blood and CSF lactate, and elevated ammonia with febrile viral infection. Heteroplasmy levels were generally variable, >68% in multiple tissues; one healthy mother had 85% heteroplasmy; and one healthy sib had 50-60% heteroplasmy (PS4_supporting; PMIDs: 8554662, 23206802, 33704825). There are no reports of de novo occurrence of this variant. This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower to undetectable levels of the variant (PP1; PMIDs: 8554662, 23206802). There are several occurrences of this variant in healthy population databases. Several studies in yeast (PMID: 31181185) support the functional impact of this variant and showed independent deleterious effects of the variant (PS3_moderate). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.69 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 Mitochondrial Disease Variant Curation Expert Panel on February 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_moderate, PS4_supporting, PP1, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.87
Hmtvar	Pathogenic	0.90
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.012	T
MutationTaster	Benign	0.98	A
GERP RS		4.9

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476136; hg19: chrM-8852;