rs199474701

Variant names:

• chrM-15967-G-A
• rs199474701
• unassigned_transcript_4820:c.57C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM6_Supporting PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The m.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID:19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy. This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID:19273760). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (78.9 percentile) and HmtVAR predicts it to be deleterious with a score of 0.65 (PP3). It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%. Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID:19273760). 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): PM6_supporting, PP3, PS3_supporting, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA120550/MONDO:0044970/015

• Frequency: Mitomap GenBank: Absent
• Consequence: TRNP unassigned_transcript_4820 synonymous
• Scores: Mitotip Pathogenic 17
• Clinical Significance: Uncertain significance reviewed by expert panel P:2 U:1 MERRF-like-disease
• Conservation: PhyloP100: -1.86
• Publications: 3 publications found

Genes affected

TRNP (HGNC:7494): (mitochondrially encoded tRNA proline)

MT-CYB (HGNC:7427): (mitochondrially encoded cytochrome b) Predicted to enable metal ion binding activity. Predicted to be involved in several processes, including electron transport coupled proton transport; response to cobalamin; and response to glucagon. Located in mitochondrion. Implicated in ovarian carcinoma and urinary bladder cancer. [provided by Alliance of Genome Resources, Apr 2022]

TRNT (HGNC:7499): (mitochondrially encoded tRNA threonine)

TRNT Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: Mitochondrial Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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.
• 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
TRNP	unassigned_transcript_4820	c.57C>T	p.Asp19Asp	synonymous_variant	Exon 1 of 1
CYTB	unassigned_transcript_4818	c.*80G>A		downstream_gene_variant
TRNT	unassigned_transcript_4819	c.*14G>A		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT-TP	ENST00000387461.2	n.57C>T		non_coding_transcript_exon_variant	Exon 1 of 1	6
MT-CYB	ENST00000361789.2	c.*80G>A		downstream_gene_variant		6		ENSP00000354554.2
MT-TT	ENST00000387460.2	n.*14G>A		downstream_gene_variant		6

Frequencies

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

Alfa AF: 0.00 Hom.: 0

Mitomap

Disease(s): MERRF-like-disease

Status: Reported

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

MELAS syndrome Pathogenic:1

Jul 12, 2019

Wong Mito Lab, Molecular and Human Genetics, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NC_012920.1:m.15967G>A variant in MT-TP gene is interpreted to be a Pathogenic variant based on the modified ACMG guidelines (unpublished). This variant meets the following evidence codes reported in the guidelines: PS3, PM7, PM8, PM9 -

MERFF syndrome Pathogenic:1

Mar 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mitochondrial disease Uncertain:1

May 13, 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.15967G>A variant in MT-TP has been reported in one individual with primary mitochondrial disease to date (PMID: 19273760). She had adult-onset myoclonic jerks, seizures, myopathy, cerebellar ataxia, hearing loss, cataracts, retinal pigmentary changes, and ragged red fibers on muscle biopsy. Brain imaging showed changes in the cerebral white matter, basal ganglia, and thalami, in addition to cerebral and cerebellar atrophy. This variant occurred de novo in the single reported individual (absent in blood and urine from mother and two healthy sisters; PM6_supporting, PMID: 19273760). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). The computational predictor MitoTIP suggests this variant is deleterious (78.9 percentile) and HmtVAR predicts it to be deleterious with a score of 0.65 (PP3). It should be noted that the low conservation of this variant (35.56% in Mitomap) is misleading due to the absence of this position in many species. Among species with a nucleotide at this position, the conservation is 84%. Single fiber testing showed higher levels of the variant in COX-deficient fibers (98.80%, standard deviation 0.89%) than in COX-positive fibers (31.1%, standard deviation 11.23%; PS3_supporting, PMID: 19273760). 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): PM6_supporting, PP3, PS3_supporting, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mitotip	Pathogenic	17
Hmtvar	Pathogenic	0.65
PhyloP100		-1.9

Other links and lift over

dbSNP: rs199474701; hg19: chrM-15968;