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rs199476133

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS1_ModeratePM1PM2PM5PP3PP5_Very_Strong

The ENST00000361899.2(MT-ATP6):c.467T>C(p.Leu156Pro) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L156R) has been classified as Likely pathogenic.

Frequency

Mitomap GenBank:
Absent

Consequence

MT-ATP6
ENST00000361899.2 missense

Scores

Apogee2
Pathogenic
0.97

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1
NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

Conservation

PhyloP100: 5.93
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PS1
Transcript ENST00000361899.2 (MT-ATP6) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM1
In a transmembrane_region Helical (size 20) in uniprot entity ATP6_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in ENST00000361899.2
PM2
No frequency data in Mitomap. Probably very rare.
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
Apogee2 supports a deletorius effect, 0.9732872 >= 0.5 .
PP5
Variant M-8993-T-C is Pathogenic according to our data. Variant chrM-8993-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 9642.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP6ATP6.1 use as main transcriptc.467T>C p.Leu156Pro missense_variant 1/1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MT-ATP6ENST00000361899.2 linkuse as main transcriptc.467T>C p.Leu156Pro 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:
0.000018
AC:
1
AN:
56431
Gnomad heteroplasmic
AF:
0.000018
AC:
1
AN:
56431

Mitomap

NARP-/-Leigh-Disease-/-MILS-/-other,NARP-/-Leigh-Disease-/-MILS-/-other

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:9Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Mitochondrial disease Pathogenic:2
Pathogenic, reviewed by expert panelcurationClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGenFeb 17, 2021The m.8993T>C (p.L156P) variant in MT-ATP6 has been reported in >16 individuals with primary mitochondrial disease with onset ranging from the first year of life to adulthood; and who had features variably consistent with Leigh syndrome and neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (PS4; PMIDs: 8395787, 16532470, 30128709, 29101127, 28003964, 26265210, 22819295, 19046652, 18055910, 16049925, 10604142). Per our literature review and a recently published review, there are no published de novo occurrences of this variant (PMID: 30763462). This variant is located at the same amino acid position as another well-known pathogenic variant, m.8993T>G (p.L156R) (PM5). 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_moderate; PMID: 10604142). In silico tools predict this variant to be pathogenic (PP3). Cybrid studies (homoplasmic for this variant) showed reduced ATP production compared to Rho+ control cell lines (PS3_supporting; PMID: 19160410). 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 February 17, 2021. Mitochondrial DNA-specific ACMG/AMP criteria applied: PS3_supporting, PS4, PM5, PP1_moderate, PP3). -
Pathogenic, no assertion criteria providedclinical testingWellcome Centre for Mitochondrial Research, Newcastle UniversityMay 22, 2017- -
NARP syndrome Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWong Mito Lab, Molecular and Human Genetics, Baylor College of MedicineOct 17, 2019The NC_012920.1:m.8993T>C (YP_003024031.1:p.Leu156Pro) 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, PS3 -
Pathogenic, no assertion criteria providedclinical testingUndiagnosed Diseases Network, NIHFeb 22, 2024- -
Leigh syndrome Pathogenic:1Other:1
Pathogenic, criteria provided, single submitterclinical testingPediatric Department, Xiangya Hospital, Central South University-- -
not provided, no classification providedliterature onlyGeneReviews-- -
Mitochondrial complex 5 (ATP synthase) deficiency, mitochondrial type 1 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInstitute of Medical Genetics and Applied Genomics, University Hospital TübingenOct 23, 2020- -
Leber optic atrophy Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -
Ataxia and polyneuropathy, adult-onset Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMDec 01, 2007- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
Apogee2
Pathogenic
0.97
Hmtvar
Pathogenic
0.90
AlphaMissense
Pathogenic
0.96
BayesDel_addAF
Uncertain
0.079
D
DEOGEN2
Uncertain
0.43
T
LIST_S2
Benign
0.69
T
MutationAssessor
Pathogenic
5.3
H
MutationTaster
Benign
1.0
A
PROVEAN
Pathogenic
-6.0
D
Sift4G
Pathogenic
0.0
D
GERP RS
4.9
Varity_R
0.99

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199476133; hg19: chrM-8994; API