NM_000237.3(LPL):c.829G>A (p.Asp277Asn) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 17, 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:: RCV001059212.4

Allele description [Variation Report for NM_000237.3(LPL):c.829G>A (p.Asp277Asn)]

NM_000237.3(LPL):c.829G>A (p.Asp277Asn)

Gene:

LPL:lipoprotein lipase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8p21.3

Genomic location:

Preferred name:

NM_000237.3(LPL):c.829G>A (p.Asp277Asn)

Other names:

D250N

HGVS:

NC_000008.11:g.19955894G>A
NG_008855.2:g.59178G>A
NM_000237.3:c.829G>AMANE SELECT
NP_000228.1:p.Asp277Asn
LRG_1298t1:c.829G>A
LRG_1298:g.59178G>A
LRG_1298p1:p.Asp277Asn
NC_000008.10:g.19813405G>A
NG_008855.1:g.21824G>A
NM_000237.2:c.829G>A
P06858:p.Asp277Asn

Protein change:

D277N; ASP250ASN

Links:

UniProtKB: P06858#VAR_004235; OMIM: 609708.0020; dbSNP: rs118204068

NCBI 1000 Genomes Browser:

rs118204068

Molecular consequence:

NM_000237.3:c.829G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV001223829	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 17, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25966443, 29748148, 30150141, 1639392, 28492532
SCV002502123	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 25, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 1639392, 30150141, 32041611, 27055971, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001223829

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 17, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002502123

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 25, 2022)

germline

clinical testing

PubMed (5)
[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	1	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

Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia.

Rabacchi C, Pisciotta L, Cefalù AB, Noto D, Fresa R, Tarugi P, Averna M, Bertolini S, Calandra S.

Atherosclerosis. 2015 Jul;241(1):79-86. doi: 10.1016/j.atherosclerosis.2015.04.815. Epub 2015 May 1.

PubMed [citation]

PMID:: 25966443

Clinical and biochemical features of different molecular etiologies of familial chylomicronemia.

Hegele RA, Berberich AJ, Ban MR, Wang J, Digenio A, Alexander VJ, D'Erasmo L, Arca M, Jones A, Bruckert E, Stroes ES, Bergeron J, Civeira F, Witztum JL, Gaudet D.

J Clin Lipidol. 2018 Jul - Aug;12(4):920-927.e4. doi: 10.1016/j.jacl.2018.03.093. Epub 2018 Apr 4.

PubMed [citation]

PMID:: 29748148

See all PubMed Citations (8)

Details of each submission

From Invitae, SCV001223829.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 277 of the LPL protein (p.Asp277Asn). This variant is present in population databases (rs118204068, gnomAD 0.005%). This missense change has been observed in individual(s) with chylomicronemia (PMID: 1639392, 25966443, 29748148, 30150141). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Asp250Asn. ClinVar contains an entry for this variant (Variation ID: 1539). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LPL protein function. Experimental studies have shown that this missense change affects LPL function (PMID: 1639392). For these reasons, this variant has been classified as 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 AiLife Diagnostics, AiLife Diagnostics, SCV002502123.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (5)

#	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		1	not provided	not provided	not provided

Last Updated: Feb 20, 2024

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