NC_012920.1(MT-TP):m.15958A>T AND Mitochondrial disease

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 23, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001090167.2

Allele description [Variation Report for NC_012920.1(MT-TP):m.15958A>T]

NC_012920.1(MT-TP):m.15958A>T

Gene:

MT-TP:mitochondrially encoded tRNA proline [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Genomic location:

Preferred name:

NC_012920.1(MT-TP):m.15958A>T

HGVS:

NC_012920.1:m.15958A>T

Links:

dbSNP: rs2068750239

NCBI 1000 Genomes Browser:

rs2068750239

Condition(s)

Name:: Mitochondrial disease
Synonyms:: Mitochondrial diseases; Mitochondrial disorder
Identifiers:: MONDO: MONDO:0044970; MeSH: D028361; MedGen: C0751651; Orphanet: 68380

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001244369	Medical Genetics, CHU Nice	no assertion criteria provided	Pathogenic (Oct 1, 2019)	not applicable	in vitro
SCV005088554	ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen	reviewed by expert panel (McCormick et al. (Hum Mutat. 2020))	Uncertain Significance (Apr 23, 2024)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 32419253, 32906214 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001244369

Medical Genetics, CHU Nice

no assertion criteria provided

Pathogenic
(Oct 1, 2019)

not applicable

in vitro

SCV005088554

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

reviewed by expert panel

(McCormick et al. (Hum Mutat. 2020))

Uncertain Significance
(Apr 23, 2024)

germline

curation

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	in vitro

Citations

PubMed

Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases.

Zereg E, Chaussenot A, Morel G, Bannwarth S, Sacconi S, Soriani MH, Attarian S, Cano A, Pouget J, Bellance R, Tranchant C, Lannes B, de Paula AM, Saadi Ait-El-Mkadem S, Chafino B, Berthet M, Fragaki K, Paquis-Flucklinger V, Rouzier C.

Hum Mutat. 2020 Aug;41(8):1394-1406. doi: 10.1002/humu.24037. Epub 2020 Jun 12.

PubMed [citation]

PMID:: 32419253

Specifications of the ACMG/AMP standards and guidelines for mitochondrial DNA variant interpretation.

McCormick EM, Lott MT, Dulik MC, Shen L, Attimonelli M, Vitale O, Karaa A, Bai R, Pineda-Alvarez DE, Singh LN, Stanley CM, Wong S, Bhardwaj A, Merkurjev D, Mao R, Sondheimer N, Zhang S, Procaccio V, Wallace DC, Gai X, Falk MJ.

Hum Mutat. 2020 Dec;41(12):2028-2057. doi: 10.1002/humu.24107. Epub 2020 Nov 10.

PubMed [citation]

PMID:: 32906214
PMCID:: PMC7717623

Details of each submission

From Medical Genetics, CHU Nice, SCV001244369.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	in vitro	not provided

Description

Exercise intolerance, myalgia, amyotrophy and mild weakness in the lower limbs, intermittent unilateral ptosis, dysarthria, failure to thrive

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	not applicable	not applicable	not provided	muscle	not provided		not provided	not provided	not provided	not provided

From ClinGen Mitochondrial Disease Nuclear and Mitochondrial Variant Curation Expert Panel, ClinGen, SCV005088554.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (2)

Description

The m.15958A>T variant in MT-TP has been reported in one individual from one family to date (PMID: 27816331), in a boy with myopathy and failure to thrive. Muscle biopsy showed ragged red fibers, COX-deficient fibers, mitochondrial proliferation, complex I deficiency, and complex IV deficiency. The variant was present at 94% heteroplasmy in muscle, 78% in urine, 48% in skin fibroblasts, 9% in blood, and was undetectable in buccal sample. The variant was undetectable in urine, blood, and buccal sample from his mother (PM6_supporting, PMID: 27816331). The computational predictor MitoTIP suggests this variant is pathogenic (93.8 percentile) and HmtVAR predicts it to be pathogenic score of 0.4 (PP3). This variant is absent in the GenBank dataset, Helix dataset, and gnomAD v3.1.2 (PM2_supporting). Single fiber testing showed higher levels of the variant in COX negative fibers (96.10% ± 1.66) than in COX positive fibers (68.78% ± 18.11), p=0.0002 (PS3_supporting, PMID: 32419253). 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): PS3_supporting, PM6_supporting, PM2_supporting, PP3.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 29, 2024

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