VCV002444342.2 - ClinVar

NM_001349206.2(LPIN1):c.1029del (p.Gln344fs)

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.

(2)

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

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.1029del (p.Gln344fs)

Variation ID: 2444342 Accession: VCV002444342.2

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2p25.1 2: 11782270 (GRCh38) [ NCBI UCSC ] 2: 11922396 (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 18, 2023	Feb 14, 2024	Jul 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001349206.2:c.1029del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001336135.1:p.Gln344fs	frameshift
NM_001261427.3:c.939del	NP_001248356.1:p.Gln314fs	frameshift
NM_001261428.3:c.1176del	NP_001248357.1:p.Gln393fs	frameshift
NM_001349199.2:c.921del	NP_001336128.1:p.Gln308fs	frameshift
NM_001349200.2:c.921del	NP_001336129.1:p.Gln308fs	frameshift
NM_001349201.2:c.921del	NP_001336130.1:p.Gln308fs	frameshift
NM_001349202.2:c.1026del	NP_001336131.1:p.Gln343fs	frameshift
NM_001349203.2:c.1026del	NP_001336132.1:p.Gln343fs	frameshift
NM_001349204.2:c.1029del	NP_001336133.1:p.Gln344fs	frameshift
NM_001349205.2:c.1029del	NP_001336134.1:p.Gln344fs	frameshift
NM_001349207.2:c.1119del	NP_001336136.1:p.Gln374fs	frameshift
NM_001349208.2:c.1068del	NP_001336137.1:p.Gln357fs	frameshift
NM_145693.4:c.921del	NP_663731.1:p.Gln308fs	frameshift
NR_146080.2:n.970del		non-coding transcript variant
NC_000002.12:g.11782272del
NC_000002.11:g.11922398del
NG_012843.2:g.109694del

... more HGVS ... less HGVS

Protein change

Q308fs, Q314fs, Q343fs, Q344fs, Q357fs, Q374fs, Q393fs

Other names

Canonical SPDI

NC_000002.12:11782269:TTT:TT

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.

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

Links

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	603	706

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.
Myoglobinuria, acute recurrent, autosomal recessive	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2023	RCV003153140.1
not provided	Pathogenic (1)	criteria provided, single submitter	Jul 22, 2023	RCV003575046.2

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.
Pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Myoglobinuria, acute recurrent, autosomal recessive Affected status: yes Allele origin: unknown	3billion Accession: SCV003841953.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Publications: PubMed (1) PubMed: 20583302 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with LPIN1 -related disorder (PMID: 20583302). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Rhabdomyolysis (present) , Decreased liver function (present) , Abnormal circulating fatty-acid concentration (present) , Elevated circulating creatine kinase concentration (present) , Cardiac arrest (present) , … (more) Rhabdomyolysis (present) , Decreased liver function (present) , Abnormal circulating fatty-acid concentration (present) , Elevated circulating creatine kinase concentration (present) , Cardiac arrest (present) , Abnormal circulating long-chain fatty-acid concentration (present) , Hepatic steatosis (present) , Renal steatosis (present) , Myocardial steatosis (present) , Ventricular arrhythmia (present) , Skeletal muscle steatosis (present) (less)
Pathogenic (Jul 22, 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: SCV004344901.1 First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 20583302‚ 28986436‚ 18817903‚ 22481384‚ 26111941 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2444342). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2444342). This premature translational stop signal has been observed in individuals with myoglobinuria (PMID: 20583302, 28986436). This variant is present in population databases (rs778562391, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Gln308Argfs*36) in the LPIN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LPIN1 are known to be pathogenic (PMID: 18817903, 20583302, 22481384, 26111941). (less)

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with LPIN1 -related disorder (PMID: 20583302). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 2444342). This premature translational stop signal has been observed in individuals with myoglobinuria (PMID: 20583302, 28986436). This variant is present in population databases (rs778562391, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Gln308Argfs*36) in the LPIN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LPIN1 are known to be pathogenic (PMID: 18817903, 20583302, 22481384, 26111941).

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
Normal human adipose tissue functions and differentiation in patients with biallelic LPIN1 inactivating mutations.	Pelosi M	Journal of lipid research	2017	PMID: 28986436
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

Text-mined citations for this variant ...

Record last updated Sep 30, 2024

ClinVar Genomic variation as it relates to human health

NM_001349206.2(LPIN1):c.1029del (p.Gln344fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...