rs199476138

Positions:

• chrM-9185-T-C
• chrM-9185-T-G

Variant summary

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

In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.90
• Clinical Significance: Pathogenic reviewed by expert panel P:14 U:1 O:1 Leigh-Disease-/-Ataxia-syndromes-/-NARP-like-disease-/-Episodic-weakness-and-Charcot-Marie-Tooth
• Conservation: PhyloP100: 7.69

Genes affected

ATP6 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: No frequency data in Mitomap. Probably very rare.
• PP5: Variant M-9185-T-C is Pathogenic according to our data. Variant chrM-9185-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9647.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP6	unassigned_transcript_4806	c.659T>C	p.Leu220Pro	missense_variant	1/1
COX3	unassigned_transcript_4807	c.-22T>C		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD4 exome Cov.: 0

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

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56421

Gnomad heteroplasmic AF: 0.000035 AC: 2 AN: 56421

Mitomap

Leigh-Disease-/-Ataxia-syndromes-/-NARP-like-disease-/-Episodic-weakness-and-Charcot-Marie-Tooth

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Nov 23, 2022	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 15, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jun 14, 2022	- -

Mitochondrial disease Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	Jun 30, 2022	The m.9185T>C (p.L220P) variant in MT-ATP6 has been reported in more than 16 individuals with features of primary mitochondrial disease with manifestations including Leigh syndrome, MELAS, NARP, neuropathy, ataxia, exercise intolerance, muscle weakness, developmental delay, and seizures (PS4; PMIDs: 28429146, 33717984, 27290639, 24153443, 27783406, 32042921, 31500933, 29116603, 31187502, 22577227, 25548692, 18461509, 17352390, 29228836, 16217706). There are at least two reports of de novo occurrences of this variant (PM6; PMIDs: 33717984, 29228836). This variant segregated with disease in multiple affected members in multiple families and several healthy family members had lower levels of the variant (PP1_moderate; PMIDs: 16217706, 17352390,20546952). This variant is absent in population databases after removing sequences from individuals with mitochondrial disease (three occurrences in GenBank sequences are from individuals with mitochondrial disease; absent in gnomAD v3.1.2 and Helix dataset; PM2_supporting). Studies in cybrids support the functional impact of this variant (PS3_supporting; PMID: 24153443). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.94 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). In summary, this variant meets criteria to be classified as pathogenic for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD U24 Mitochondrial Disease Variant Curation Expert Panel on May 20, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS4, PM6, PS3_supporting, PP1_moderate, PM2_supporting, PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Wellcome Centre for Mitochondrial Research, Newcastle University	May 22, 2017	- -

NARP syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 24, 2024	Criteria applied: PS4,PM6,PP1_MOD,PS3_SUP,PM2_SUP,PP3 -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -

Leber optic atrophy Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

Leigh syndrome Pathogenic:1 Other:1

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.9185T>C (YP_003024031.1:p.Leu220Pro) variant in MTATP6 gene is interpretated to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes: PS1, PM9, PM10, PP3, PP4 -
not provided, no classification provided	literature only	GeneReviews	-	- -

Charcot-Marie-Tooth disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GeneReviews

Sep 01, 2016

- -

Charcot-Marie-Tooth disease, type IA Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 12, 2022

- -

Mitochondrial DNA-Associated Leigh Syndrome and NARP Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jul 11, 2022

_x000D_This variant was identified as homoplasmic. Criteria applied: PS2, PS4, PP1_MOD, PP3, PM2_SUP -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.90
Hmtvar	Pathogenic	0.89
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.081	D
DEOGEN2	Benign	0.32	T
LIST_S2	Benign	0.65	T
MutationAssessor	Pathogenic	5.3	H
PROVEAN	Pathogenic	-6.2	D
Sift4G	Pathogenic	0.0	D
GERP RS		5.0
Varity_R		0.99

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199476138; hg19: chrM-9186;