rs794726857

Variant names:

• chrM-8969-G-A
• rs794726857
• ENST00000361899.2:c.443G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-8969-G-A
• chrM-8969-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS4_Moderate PS2_Moderate PP1_Moderate PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA199769/MONDO:0044970/014

• Frequency: Mitomap GenBank: Absent
• Consequence: MT-ATP6 ENST00000361899.2 missense
• Scores: Apogee2 Pathogenic 0.84
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 Mitochondrial-myopathy+-lactic-acidosis-and-sideroblastic-anemia-(MLASA)-/-IgG-nephropathy,Suspected-mito-disease
• Conservation: PhyloP100: 9.61
• Publications: 10 publications found

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-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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361899.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MT-ATP6	ENST00000361899.2	TSL:6	c.443G>A	p.Ser148Asn	missense	Exon 1 of 1	ENSP00000354632.2
	MT-CO3	ENST00000362079.2	TSL:6	c.-238G>A		upstream_gene	N/A	ENSP00000354982.2

Frequencies

Mitomap GenBank The variant is not present, suggesting it is rare .

Gnomad homoplasmic AF: 0.0 AC: 0 AN: 56424

Gnomad heteroplasmic AF: 0.000071 AC: 4 AN: 56424

Mitomap

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

Status: Cfrm-[LP],Reported

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Leber optic atrophy (1)
1	-	-	MELAS syndrome (1)
1	-	-	Mitochondrial disease (1)
1	-	-	MT-ATP6-related disorder (1)
1	-	-	Myopathy, lactic acidosis, and sideroblastic anemia 3 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		9.6
PROVEAN	Uncertain	-2.8	D
Sift4G	Pathogenic	0.0	D
GERP RS		4.9
Varity_R		0.94
Mutation Taster		=42/158	disease causing

Other links and lift over

dbSNP: rs794726857; hg19: chrM-8970; COSMIC: COSV106107896; COSMIC: COSV106107896;