rs199474818

Variant names:

• chrM-7445-A-C
• rs199474818
• ENST00000361624.2:c.1542A>C

Your query was ambiguous. Multiple possible variants found:

• chrM-7445-A-C
• chrM-7445-A-G
• chrM-7445-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS4_Moderate PS3_Supporting PM5_Supporting

This summary comes from the ClinGen Evidence Repository: The m.7445A>C (p.*514S) variant in MT-CO1 has been reported in five unrelated individuals with primary mitochondrial disease to date (PS4_moderate; PMIDs: 10577941, 17659260, 18639500, 19705751). These individuals were of Asian background and had childhood onset hearing loss. Some had hearing loss after illness and in others no precipitating event could be identified. The variant was present at homoplasmy in these individuals. Detailed family history information was not provided in several cases. One family had three affected siblings however all were homoplasmic, precluding consideration for PP1 (PMID:19705751). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.028%; Helix's 196,554 sequences: AF=0.001%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Functional studies showed inefficient processing by tRNAseZ in the presence of this variant (PS3_supporting; PMID:16361254). Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_moderate, PS3_supporting, PM5_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA340923/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 17)
• Consequence: MT-CO1 ENST00000361624.2 stop_lost, splice_region
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 O:1 DEAF,SNHL,SNHL
• Conservation: PhyloP100: -0.943
• Publications: 5 publications found

Genes affected

MT-CO1 (HGNC:7419): (mitochondrially encoded cytochrome c oxidase I) Contributes to cytochrome-c oxidase activity. Predicted to be involved in electron transport coupled proton transport and mitochondrial electron transport, cytochrome c to oxygen. Part of mitochondrial respiratory chain complex III and mitochondrial respiratory chain complex IV. [provided by Alliance of Genome Resources, Apr 2022]

MT-CO2 (HGNC:7421): (mitochondrially encoded cytochrome c oxidase II) Contributes to cytochrome-c oxidase activity. Predicted to be involved in mitochondrial electron transport, cytochrome c to oxygen and positive regulation of vasoconstriction. Located in mitochondrial inner membrane. Part of respiratory chain complex IV. Biomarker of Huntington's disease and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRND (HGNC:7478): (mitochondrially encoded tRNA aspartic acid)

TRNS1 (HGNC:7497): (mitochondrially encoded tRNA serine 1 (UCN))

TRNS1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen
• MERRF syndrome

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COX1	unassigned_transcript_4799	c.1542A>C	p.Ter514Serext*?	stop_lost, splice_region_variant	Exon 1 of 1
COX2	unassigned_transcript_4802	c.-141A>C		upstream_gene_variant
TRND	unassigned_transcript_4801	c.-73A>C		upstream_gene_variant
TRNS1	unassigned_transcript_4800	c.*1T>G		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-CO1	ENST00000361624.2	c.1542A>C	p.Ter514Serext*?	stop_lost, splice_region_variant	Exon 1 of 1	6		ENSP00000354499.2
MT-CO2	ENST00000361739.1	c.-141A>C		upstream_gene_variant		6		ENSP00000354876.1
MT-TD	ENST00000387419.1	n.-73A>C		upstream_gene_variant		6
MT-TS1	ENST00000387416.2	n.*1T>G		downstream_gene_variant		6

Frequencies

Mitomap GenBank AF: 0.00030 AC: 17

Mitomap

Disease(s): DEAF,SNHL,SNHL

Status: Reported,Cfrm-[P],Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:2 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 14, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mitochondrial disease Uncertain:1

Jul 08, 2024

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

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The m.7445A>C (p.*514S) variant in MT-CO1 has been reported in five unrelated individuals with primary mitochondrial disease to date (PS4_moderate; PMIDs: 10577941, 17659260, 18639500, 19705751). These individuals were of Asian background and had childhood onset hearing loss. Some had hearing loss after illness and in others no precipitating event could be identified. The variant was present at homoplasmy in these individuals. Detailed family history information was not provided in several cases. One family had three affected siblings however all were homoplasmic, precluding consideration for PP1 (PMID: 19705751). This variant is present in population databases (Mitomap's 51,863 sequences: AF=0.028%; Helix's 196,554 sequences: AF=0.001%; gnomAD v3.1.2: absent). There are no in-silico prediction tools for a stop-loss variant in mitochondrial DNA, although this variant would not be expected to cause run-through due to the excision of the tRNA immediately adjacent. Functional studies showed inefficient processing by tRNAseZ in the presence of this variant (PS3_supporting; PMID: 16361254). Another variant at this position has been classified as pathogenic – m.7445A>G (PM5_supporting). In summary, this variant meets criteria to be classified as uncertain significance for primary mitochondrial disease inherited in a mitochondrial manner. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Variant Curation Expert Panel on July 8, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_moderate, PS3_supporting, PM5_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.33	T
PhyloP100		-0.94
GERP RS		-0.79
Varity_R		0.24

Other links and lift over

dbSNP: rs199474818; hg19: chrM-7446;