NM_133259.4(LRPPRC):c.864+2T>C AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 2, 2023
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:: RCV000197365.6

Allele description [Variation Report for NM_133259.4(LRPPRC):c.864+2T>C]

NM_133259.4(LRPPRC):c.864+2T>C

Gene:

LRPPRC:leucine rich pentatricopeptide repeat containing [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2p21

Genomic location:

Preferred name:

NM_133259.4(LRPPRC):c.864+2T>C

HGVS:

NC_000002.12:g.43975089A>G
NG_008247.1:g.25917T>C
NM_133259.4:c.864+2T>CMANE SELECT
NC_000002.11:g.44202228A>G
NM_133259.3:c.864+2T>C

Links:

dbSNP: rs863224053

NCBI 1000 Genomes Browser:

rs863224053

Molecular consequence:

NM_133259.4:c.864+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000251666	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jan 29, 2013)	germline	clinical testing	Citation Link,
SCV001575347	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 26510951, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000251666

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Jan 29, 2013)

germline

clinical testing

Citation Link,

SCV001575347

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 2, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

LRPPRC mutations cause early-onset multisystem mitochondrial disease outside of the French-Canadian population.

Oláhová M, Hardy SA, Hall J, Yarham JW, Haack TB, Wilson WC, Alston CL, He L, Aznauryan E, Brown RM, Brown GK, Morris AA, Mundy H, Broomfield A, Barbosa IA, Simpson MA, Deshpande C, Moeslinger D, Koch J, Stettner GM, Bonnen PE, Prokisch H, et al.

Brain. 2015 Dec;138(Pt 12):3503-19. doi: 10.1093/brain/awv291. Epub 2015 Oct 27.

PubMed [citation]

PMID:: 26510951
PMCID:: PMC4655343

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000251666.10

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

Description

c.864+2 T>C: IVS7+2 T>C in intron 7 of the LRPPRC gene (NM_133259.3). The c.864+2 T>C splice site mutation in the LRPPRC gene destroys the canonical splice donor site in intron 7. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Although this mutation has not been previously reported to our knowledge, it is predicted to be a pathogenic mutation. The variant is found in MITONUC-MITOP panel(s).

#	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, SCV001575347.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects a donor splice site in intron 7 of the LRPPRC 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 LRPPRC are known to be pathogenic (PMID: 26510951). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LRPPRC-related conditions. ClinVar contains an entry for this variant (Variation ID: 214601). 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

Last Updated: Sep 29, 2024

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