NM_002437.5(MPV17):c.186+2T>C AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000195573.12

Allele description [Variation Report for NM_002437.5(MPV17):c.186+2T>C]

NM_002437.5(MPV17):c.186+2T>C

Gene:

MPV17:mitochondrial inner membrane protein MPV17 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p23.3

Genomic location:

Preferred name:

NM_002437.5(MPV17):c.186+2T>C

HGVS:

NC_000002.12:g.27312992A>G
NG_008075.1:g.14573T>C
NG_008075.2:g.15105T>C
NG_033055.1:g.272T>C
NG_033055.2:g.453T>C
NM_002437.5:c.186+2T>CMANE SELECT
NC_000002.11:g.27535859A>G
NM_002437.4:c.186+2T>C

Links:

dbSNP: rs147952488

NCBI 1000 Genomes Browser:

rs147952488

Molecular consequence:

NM_002437.5:c.186+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Gene ID:106495921

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ATP6V0A2 [Apteryx mantelli]
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Gene ID:106497686

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251737	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 9, 2020)	germline	clinical testing	Citation Link,
SCV001377454	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 23714749, 20074988, 28492532
SCV003819630	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251737

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 9, 2020)

germline

clinical testing

Citation Link,

SCV001377454

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 24, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV003819630

Revvity Omics, Revvity

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 23, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Clinical, biochemical, cellular and molecular characterization of mitochondrial DNA depletion syndrome due to novel mutations in the MPV17 gene.

Uusimaa J, Evans J, Smith C, Butterworth A, Craig K, Ashley N, Liao C, Carver J, Diot A, Macleod L, Hargreaves I, Al-Hussaini A, Faqeih E, Asery A, Al Balwi M, Eyaid W, Al-Sunaid A, Kelly D, van Mourik I, Ball S, Jarvis J, Mulay A, et al.

Eur J Hum Genet. 2014 Feb;22(2):184-91. doi: 10.1038/ejhg.2013.112. Epub 2013 May 29.

PubMed [citation]

PMID:: 23714749
PMCID:: PMC3895632

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV000251737.13

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 29318572, 23137571, 29282788, 22593919, 20074988)

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001377454.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change affects a donor splice site in intron 3 of the MPV17 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MPV17 are known to be pathogenic (PMID: 23714749). This variant is present in population databases (rs147952488, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with mitochondrial DNA depletion syndrome (PMID: 20074988). ClinVar contains an entry for this variant (Variation ID: 38347). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#	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

From Revvity Omics, Revvity, SCV003819630.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	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: Sep 29, 2024

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