M-5532-G-A

Variant names:

• chrM-5532-G-A
• rs199474674
• unassigned_transcript_4794:c.21G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PS3_Supporting PP1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.5532G>A variant in MT-TW has been reported in one individual with primary mitochondrial disease to date (PMID:15054399), in a 16-year-old girl with failure to thrive, short stature, recurrent vomiting, developmental delay and regression, ophthalmoplegia, ptosis, pigmentary retinopathy, sensorineural hearing loss, and myopathy. Brain imaging showed generalized atrophy and periventricular white matter changes. Elevated lactate was seen in blood and cerebrospinal fluid. Muscle biopsy showed ragged red fibers and mitochondrial respiratory chain complex I and IV deficiency. The variant was present at 92% heteroplasmy in muscle, 37% in fibroblasts, and 21% in blood. The variant was present at lower heteroplasmy levels in blood from her healthy mother (7%) and brother (9%; PP1; PMID:15054399). There are no other individuals or families reported in the medical literature. Although there is one occurrence of this variant in population databases (1/61,134 in MITOMAP, absent in Helix and gnomad v3.1.2), the frequency is still low (PM2_supporting). In silico predictors are conflicting as the computational predictor MitoTIP suggests this variant is likely benign (19.4 percentile) but HmtVAR predicts it to be deleterious with a score of 0.7. Single fiber testing showed higher levels of the variant in COX-negative fibers (>90%) than in COX-positive fibers (6-85%, p<0.0001, PS3_supporting, PMID:15054399). 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 May 13, 2024. Mitochondrial DNA-specific ACMG/AMP criteria applied (PMID:32906214): PP1, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120542/MONDO:0044970/015

• Frequency: Mitomap GenBank: 𝑓 0.0 (AC: 1)
• Consequence: TRNW unassigned_transcript_4794 synonymous
• Scores: Mitotip Benign 7.4
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 Gastrointestinal-Syndrome
• Conservation: PhyloP100: 4.17
• Publications: 1 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.

• PS3: 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000387382.1. 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-TW	ENST00000387382.1	TSL:6	n.21G>A		non_coding_transcript_exon	Exon 1 of 1
	MT-ND2	ENST00000361453.3	TSL:6	c.*21G>A		downstream_gene	N/A	ENSP00000355046.4
	MT-TA	ENST00000387392.1	TSL:6	n.*55C>T		downstream_gene	N/A

Frequencies

Mitomap GenBank AF: 0.0 AC: 1

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): Gastrointestinal-Syndrome

Status: Reported

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	MELAS syndrome (1)
-	1	-	Mitochondrial disease (1)
1	-	-	Neurogastrointestinal syndrome, mitochondrial (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
Mitotip	Benign	7.4
Hmtvar	Pathogenic	0.70
PhyloP100		4.2

Other links and lift over

dbSNP: rs199474674; hg19: chrM-5533;