rs727504555

Variant names:

• chrM-1027-A-G
• rs727504555
• ENST00000389680.2:n.380A>G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The m.1027A>G variant in MT-RNR1 has been reported in six unrelated individuals with primary mitochondrial disease. All had hearing loss (4/6 had aminoglycoside exposure; PMIDs: 21205314, 20100600). The variant was present at homoplasmy in both affected and unaffected individuals from these families. There are no de novo occurrences of this variant to our knowledge. This variant is present in population databases (MITOMAP: 0.028%; gnomAD v3.1.2: 0.025%; Helix: 0.037%). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): None. LINK:https://erepo.genome.network/evrepo/ui/classification/CA273573/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.00030 (AC: 18)
• Consequence: MT-RNR1 ENST00000389680.2 non_coding_transcript_exon
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 DEAF-associated
• Conservation: PhyloP100: 1.04
• Publications: 0 publications found

Genes affected

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MT-RNR1 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNR1	unassigned_transcript_4785	n.380A>G		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-RNR1	ENST00000389680.2	n.380A>G		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

Mitomap GenBank AF: 0.00030 AC: 18

Gnomad homoplasmic AF: 0.00025 AC: 14 AN: 56428

Gnomad heteroplasmic AF: 0.0 AC: 0 AN: 56428

Mitomap

Disease(s): DEAF-associated

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Aug 08, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 1027A>G variant in MTRNR1 has been reported in five Chinese individuals with severe to profound hearing loss (four of whom were exposed to aminoglycosides), and the variant was absent from 449 ethnically matched controls (Shen 2011, Lu 2010). The variant segregated with disease in two maternal relatives (consistent with a mitochondrial inheritance pattern) of an additional Chinese proband with severe hearing loss who was not exposed to aminoglycosides (Shen 2011). This v ariant has not been reported in the Human Mitochondrial Genome Database, which i ncludes a total of 2704 mitochondrial genomes of which 52 are from Chinese indiv iduals (www.mtdb.igp.uu.se). In summary, this variant is likely pathogenic based on the observation of the variant in individuals with hearing loss, though addi tional studies are required to fully establish its clinical significance. -

Mitochondrial disease Uncertain:1

Aug 12, 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.1027A>G variant in MT-RNR1 has been reported in six unrelated individuals with primary mitochondrial disease. All had hearing loss (4/6 had aminoglycoside exposure; PMIDs: 21205314, 20100600). The variant was present at homoplasmy in both affected and unaffected individuals from these families. There are no de novo occurrences of this variant to our knowledge. This variant is present in population databases (MITOMAP: 0.028%; gnomAD v3.1.2: 0.025%; Helix: 0.037%). There are no in silico predictors for this type of variant in mitochondrial DNA. There are no cybrids, single fiber studies, or other functional assays reported on this variant. 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 August 12, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): None. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0

Other links and lift over

dbSNP: rs727504555; hg19: chrM-1029;