rs199474671

Variant names:

• chrM-5549-G-A
• rs199474671
• unassigned_transcript_4794:c.38G>A

Your query was ambiguous. Multiple possible variants found:

• chrM-5549-G-A
• chrM-5549-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM6_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5549G>A variant in MT-TW has been reported in two individuals with primary mitochondrial disease to date (PMIDs: 7695240, 34276539; PS4_supporting). The first reported case was a man with onset at age 40 years of personality and behavioral changes followed by progressive cognitive decline, hearing loss, ataxia, chorea, dysarthria, and axonal neuropathy, and he died at age 53 years (PMID:7695240). Brain imaging showed atrophy of the cerebrum, cerebellum, and brainstem. Muscle biopsy showed COX-negative and ragged red fibers. The variant was present at 40% heteroplasmy in blood, 83-86% in skeletal muscle, and 51-93% in organs on autopsy (liver, optic nerve, lung, heart, kidney, cerebral cortex, cerebellum). There was no mention of testing in family members. The second reported case was a 26-year-old man with onset in adolescence of epilepsy, ataxia, dystonia, impaired cognition, and hearing loss (PMID:34276539). Brain imaging showed leukoencephalopathy and cerebral atrophy in addition to calcifications of the bilateral basal ganglia, thalamus, and cerebellar dentate nuclei. Muscle biopsy showed ragged blue and COX-deficient fibers. The variant was present at 5.4% heteroplasmy in blood and 61.5% in muscle. The variant was absent in his mother’s blood (PMID:34276539; PM6_supporting). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (88.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.35 (PP3). 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PS4_supporting, PM6_supporting, PM2_supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120540/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNW unassigned_transcript_4794 missense
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:1 DEMCHO-/-mitochondrial-encephalomyopathy
• Conservation: PhyloP100: 5.29
• Publications: 2 publications found

Genes affected

TRNW (HGNC:7501): (mitochondrially encoded tRNA tryptophan)

MT-ND2 (HGNC:7456): (mitochondrially encoded NADH dehydrogenase 2) Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Part of mitochondrial respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; multiple sclerosis; myocardial infarction; neurodegenerative disease (multiple); and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNN (HGNC:7493): (mitochondrially encoded tRNA asparagine)

TRNA (HGNC:7475): (mitochondrially encoded tRNA alanine)

TRNC (HGNC:7477): (mitochondrially encoded tRNA cysteine)

TRNC Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM6: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNW	unassigned_transcript_4794	c.38G>A	p.Ser13Asn	missense_variant	Exon 1 of 1
ND2	unassigned_transcript_4793	c.*38G>A		downstream_gene_variant
TRNN	unassigned_transcript_4796	c.*108C>T		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-ND2	ENST00000361453.3	c.*38G>A		downstream_gene_variant		6		ENSP00000355046.4

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): DEMCHO-/-mitochondrial-encephalomyopathy

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Mitochondrial encephalopathy Pathogenic:1

Mar 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

Apr 23, 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.5549G>A variant in MT-TW has been reported in two individuals with primary mitochondrial disease to date (PMIDs: 7695240, 34276539; PS4_supporting). The first reported case was a man with onset at age 40 years of personality and behavioral changes followed by progressive cognitive decline, hearing loss, ataxia, chorea, dysarthria, and axonal neuropathy, and he died at age 53 years (PMID: 7695240). Brain imaging showed atrophy of the cerebrum, cerebellum, and brainstem. Muscle biopsy showed COX-negative and ragged red fibers. The variant was present at 40% heteroplasmy in blood, 83-86% in skeletal muscle, and 51-93% in organs on autopsy (liver, optic nerve, lung, heart, kidney, cerebral cortex, cerebellum). There was no mention of testing in family members. The second reported case was a 26-year-old man with onset in adolescence of epilepsy, ataxia, dystonia, impaired cognition, and hearing loss (PMID: 34276539). Brain imaging showed leukoencephalopathy and cerebral atrophy in addition to calcifications of the bilateral basal ganglia, thalamus, and cerebellar dentate nuclei. Muscle biopsy showed ragged blue and COX-deficient fibers. The variant was present at 5.4% heteroplasmy in blood and 61.5% in muscle. The variant was absent in his mother’s blood (PMID: 34276539; PM6_supporting). This variant is absent in the MITOMAP GenBank dataset, gnomAD v3.1.2, and the Helix dataset (PM2_supporting). The computational predictor MitoTIP suggests this variant is pathogenic (88.3 percentile) and HmtVAR predicts it to be pathogenic with a score of 0.35 (PP3). 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 April 23, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID: 32906214): PS4_supporting, PM6_supporting, PM2_supporting, PP3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Benign	0.35
PhyloP100		5.3
Mutation Taster		=89/11	polymorphism

Other links and lift over

dbSNP: rs199474671; hg19: chrM-5550; COSMIC: COSV104419736;