rs199476138

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM6PS4PS3_SupportingPP1_ModeratePP3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340928/MONDO:0044970/014

Frequency

Mitomap GenBank:

Absent

Consequence

MT-ATP6
ENST00000361899.2 missense

Scores

Apogee2

Pathogenic

0.90

Clinical Significance

Pathogenic reviewed by expert panel P:16U:1O:1

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

Conservation

PhyloP100: 7.69

Publications

36 publications found

Variant links:

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-ATP6 links:

MT-CO3 (HGNC:7422): (mitochondrially encoded cytochrome c oxidase III) Predicted to enable electron transfer activity and oxidoreduction-driven active transmembrane transporter activity. Involved in respiratory chain complex IV assembly. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO3 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
hereditary recurrent myoglobinuria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
cytochrome-c oxidase deficiency disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Leber hereditary optic neuropathy
Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
Leigh syndrome
Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

MT-CO3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 11 ACMG points.

PS3

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.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP6	unassigned_transcript_4805	c.659T>C	p.Leu220Pro	missense_variant	Exon 1 of 1
COX3	unassigned_transcript_4806	c.-22T>C		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ATP6	ENST00000361899.2 link	c.659T>C	p.Leu220Pro	missense_variant	Exon 1 of 1	6		ENSP00000354632.2
MT-CO3	ENST00000362079.2 link	c.-22T>C		upstream_gene_variant		6		ENSP00000354982.2

Frequencies

Mitomap GenBank

The variant is not present, suggesting it is rare.

Gnomad homoplasmic

AF:

0.0

AC:

AN:

56421

Gnomad heteroplasmic

AF:

0.000035

AC:

AN:

56421

Alfa

AF:

0.00

Hom.:

Mitomap

Disease(s): Leigh-Disease-/-Ataxia-syndromes-/-NARP-like-disease-/-Episodic-weakness-and-Charcot-Marie-Tooth

Status: Cfrm-[P]

Publication(s):

16217706

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16Uncertain:1Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 23, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:3

Jun 14, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 28, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is not observed in the gnomAD v3.1.2 dataset. Predicted Consequence/Location: Missense variant Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 24153443). In silico tool predictions suggest damaging effect of the variant on gene or gene product (APOGEE: 0.94 >=0.5) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (3billion dataset/ClinVar ID: VCV000009647). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 16217706, 17352390, 18461509, 22577227, 24153443, 25548692, 27290639, 27783406, 28429146, 29116603, 29228836, 31187502, 31500933, 32042921, 33717984). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 29228836, 33717984). The variant has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 16217706, 17352390, 20546952). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Mitochondrial disease

Pathogenic:2

May 22, 2017

Wellcome Centre for Mitochondrial Research, Newcastle University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 30, 2022

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

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

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. -

NARP syndrome

Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Sep 24, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PS4,PM6,PP1_MOD,PS3_SUP,PM2_SUP,PP3 -

Leber optic atrophy

Pathogenic:2

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Leigh syndrome

Pathogenic:1Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Oct 17, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Charcot-Marie-Tooth disease

Pathogenic:1

Sep 01, 2016

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Charcot-Marie-Tooth disease, type IA

Pathogenic:1

Sep 12, 2022

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial DNA-Associated Leigh Syndrome and NARP

Pathogenic:1

Jul 11, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

_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

DEOGEN2

Benign

0.32

LIST_S2

Benign

0.65

MutationAssessor

Pathogenic

5.3

PhyloP100

7.7

PROVEAN

Pathogenic

-6.2

Sift4G

Pathogenic

0.0

GERP RS

5.0

Varity_R

0.99

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Mitomap

ClinVar

Submissions by phenotype

Computational scores

Publications

Other links and lift over