rs794726857

Positions:

• chrM-8969-G-A
• chrM-8969-G-C

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 Likely pathogenic (★★★).

• Frequency: Mitomap GenBank: Absent
• Consequence: ATP6 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease
• Conservation: PhyloP100: 9.61

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-8969-G-A is Pathogenic according to our data. Variant chrM-8969-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191364.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.443G>A	p.Ser148Asn	missense_variant	1/1

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: 56424

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56424

Mitomap

Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Myopathy, lactic acidosis, and sideroblastic anemia 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2014

- -

Mitochondrial disease Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

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

Jun 30, 2022

The m.8969G>A (p.S148N) variant in MT-ATP6 has been reported in at least five individuals from four families in the literature with features including nephrotic syndrome, developmental delay, seizures, stroke-like episodes, muscle weakness, brain atrophy, agenesis of the corpus callosum, hearing loss, Wolff-Parkinson-White syndrome, increased fasting level of glucose, liver steatosis, and failure to thrive, with heteroplasmy levels ranging from 61-96% (PS4_moderate; PMIDs: 25037980, 29350304, 27812026, 27450679). Additionally, this expert panel knew of two local families with affected individuals with this variant that the expert panel agreed to include. The variant was de novo in two of the four families reported in the literature (PS2_moderate; PMIDs: 25037980, 27450679). This variant segregated with disease in multiple affected members in one family and several healthy family members had lower to undetectable levels of the variant (PP1_moderate; PMIDs: 29350304). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Studies in cybrids and yeast support the functional impact of this variant (PS3_supporting; PMID: 27812026). The computational predictor APOGEE gives a consensus rating of pathogenic with a score of 0.57 (Min=0, Max=1), which predicts a damaging effect on gene function (PP3). 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 Mitochondrial Disease Variant Curation Expert Panel on March 28, 2022. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS2_moderate, PP1_moderate, PM2_supporting, PS3_supporting, PP3. -

MELAS syndrome Pathogenic: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.8969G>A (YP_003024031.1:p.Ser148Asn) 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 -

Leber optic atrophy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Apogee2	Pathogenic	0.84
Hmtvar	Pathogenic	0.81
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	0.0045	T
DEOGEN2	Benign	0.33	T
LIST_S2	Benign	0.77	T
MutationAssessor	Pathogenic	5.3	H
PROVEAN	Uncertain	-2.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.9
Varity_R		0.94

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs794726857; hg19: chrM-8970;