NM_001040716.2(PC):c.1826-1G>C AND Pyruvate carboxylase deficiency

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Sep 19, 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:: RCV003476627.3

Allele description [Variation Report for NM_001040716.2(PC):c.1826-1G>C]

NM_001040716.2(PC):c.1826-1G>C

Gene:

PC:pyruvate carboxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.2

Genomic location:

Preferred name:

NM_001040716.2(PC):c.1826-1G>C

HGVS:

NC_000011.10:g.66851947C>G
NG_008319.1:g.111430G>C
NM_000920.4:c.1826-1G>C
NM_001040716.2:c.1826-1G>CMANE SELECT
NM_022172.3:c.1826-1G>C
NC_000011.9:g.66619418C>G

Molecular consequence:

NM_000920.4:c.1826-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_001040716.2:c.1826-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_022172.3:c.1826-1G>C - splice acceptor variant - [Sequence Ontology: SO:0001574]

Condition(s)

Name:: Pyruvate carboxylase deficiency
Synonyms:: ATAXIA WITH LACTIC ACIDOSIS II; PC deficiency; Ataxia with lactic acidosis 2; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009949; MedGen: C0034341; Orphanet: 3008; OMIM: 266150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004202818	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 10, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004619185	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 19, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16199547, 12112657, 19306334, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004202818

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Apr 10, 2023)

unknown

clinical testing

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

SCV004619185

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 19, 2023)

germline

clinical testing

PubMed (4)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (5)

Details of each submission

From Baylor Genetics, SCV004202818.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004619185.1

#	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 an acceptor splice site in intron 14 of the PC 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 PC are known to be pathogenic (PMID: 12112657, 19306334). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PC-related conditions. 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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