VCV001465375.6 - ClinVar

NM_001349206.2(LPIN1):c.1807-2A>G

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001349206.2(LPIN1):c.1807-2A>G

Variation ID: 1465375 Accession: VCV001465375.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p25.1 2: 11795406 (GRCh38) [ NCBI UCSC ] 2: 11935532 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 28, 2022	Feb 14, 2024	Dec 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001349206.2:c.1807-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001261427.3:c.1717-2A>G		splice acceptor
NM_001261428.3:c.1954-2A>G		splice acceptor
NM_001349199.2:c.1699-2A>G		splice acceptor
NM_001349200.2:c.1777-2A>G		splice acceptor
NM_001349201.2:c.1777-2A>G		splice acceptor
NM_001349202.2:c.1804-2A>G		splice acceptor
NM_001349203.2:c.1804-2A>G		splice acceptor
NM_001349204.2:c.1807-2A>G		splice acceptor
NM_001349205.2:c.1807-2A>G		splice acceptor
NM_001349207.2:c.1897-2A>G		splice acceptor
NM_001349208.2:c.1846-2A>G		splice acceptor
NM_145693.4:c.1699-2A>G		splice acceptor
NC_000002.12:g.11795406A>G
NC_000002.11:g.11935532A>G
NG_012843.2:g.122828A>G

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:11795405:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00040 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00028

1000 Genomes Project 30x 0.00031

1000 Genomes Project 0.00040

Links

dbSNP: rs533651991 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LPIN1		-	-	GRCh38 GRCh37	602	705

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV001990266.5
Myoglobinuria, acute recurrent, autosomal recessive	Likely pathogenic (1)	criteria provided, single submitter	Dec 29, 2021	RCV002497902.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Dec 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myoglobinuria, acute recurrent, autosomal recessive Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002779647.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Nov 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226539.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 35242575 Comment: PM2, PVS1 Number of individuals with the variant: 1
Pathogenic (Dec 26, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002249553.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16199547‚ 18817903‚ 20583302‚ 22481384‚ 26111941‚ 35242575 Comment: This sequence change affects an acceptor splice site in intron 12 of the LPIN1 gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more) This sequence change affects an acceptor splice site in intron 12 of the LPIN1 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 LPIN1 are known to be pathogenic (PMID: 18817903, 20583302, 22481384, 26111941). This variant is present in population databases (rs533651991, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive myoglobinuria (PMID: 35242575; Invitae). ClinVar contains an entry for this variant (Variation ID: 1465375). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change affects an acceptor splice site in intron 12 of the LPIN1 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 LPIN1 are known to be pathogenic (PMID: 18817903, 20583302, 22481384, 26111941). This variant is present in population databases (rs533651991, gnomAD 0.006%). Disruption of this splice site has been observed in individuals with clinical features of autosomal recessive myoglobinuria (PMID: 35242575; Invitae). ClinVar contains an entry for this variant (Variation ID: 1465375). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
LPIN1 rhabdomyolysis: A single site cohort description and treatment recommendations.	Kanderi N	Molecular genetics and metabolism reports	2022	PMID: 35242575
A novel therapeutic approach for LPIN1 mutation-associated rhabdomyolysis--The Austrian experience.	Pichler K	Muscle & nerve	2015	PMID: 26111941
Study of LPIN1, LPIN2 and LPIN3 in rhabdomyolysis and exercise-induced myalgia.	Michot C	Journal of inherited metabolic disease	2012	PMID: 22481384
LPIN1 gene mutations: a major cause of severe rhabdomyolysis in early childhood.	Michot C	Human mutation	2010	PMID: 20583302
Mutations in LPIN1 cause recurrent acute myoglobinuria in childhood.	Zeharia A	American journal of human genetics	2008	PMID: 18817903
Splicing in action: assessing disease causing sequence changes.	Baralle D	Journal of medical genetics	2005	PMID: 16199547

Text-mined citations for rs533651991 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001349206.2(LPIN1):c.1807-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs533651991 ...