NM_000237.3(LPL):c.644G>A (p.Gly215Glu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jan 29, 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:: RCV000521241.17

Allele description [Variation Report for NM_000237.3(LPL):c.644G>A (p.Gly215Glu)]

NM_000237.3(LPL):c.644G>A (p.Gly215Glu)

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.644G>A (p.Gly215Glu)

Other names:

G188E

HGVS:

NC_000008.11:g.19954222G>A
NG_008855.2:g.57506G>A
NM_000237.3:c.644G>AMANE SELECT
NP_000228.1:p.Gly215Glu
LRG_1298t1:c.644G>A
LRG_1298:g.57506G>A
LRG_1298p1:p.Gly215Glu
NC_000008.10:g.19811733G>A
NG_008855.1:g.20152G>A
NM_000237.2:c.644G>A
NM_000237.3(LPL):c.644G>AMANE SELECT
P06858:p.Gly215Glu

Protein change:

G215E; GLY188GLU

Links:

UniProtKB: P06858#VAR_004225; OMIM: 609708.0002; dbSNP: rs118204057

NCBI 1000 Genomes Browser:

rs118204057

Molecular consequence:

NM_000237.3:c.644G>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
SCV000617843	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 22, 2022)	germline	clinical testing	Citation Link,
SCV000935254	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22095987, 28438574, 1400331, 1969408, 29288010, 28492532
SCV001923354	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001959948	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV002503124	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 21, 2022)	germline	clinical testing	PubMed (21) [See all records that cite these PMIDs] 1969408, 30150141, 28438574, 24747307, 29288010, 31589614, 24793350, 32041611, 33303402, 1400331, 29748148, 1351946, 24503134, 32472350, 1975597, 22095987, 27055971, 18922999, 30210108, 12905705, 25741868
SCV003823435	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 25, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226795	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 14, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 10359734, 1351946, 1400331, 1619366, 1969408, 1975597, 22095987, 24747307, 24793350, 27055971, 29748148, 30352774, 34363016, 35837325, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Molecular basis of the familial chylomicronemia syndrome in patients from the National Dyslipidemia Registry of the Spanish Atherosclerosis Society.

Ariza MJ, Rioja J, Ibarretxe D, Camacho A, Díaz-Díaz JL, Mangas A, Carbayo-Herencia JA, Ruiz-Ocaña P, Lamíquiz-Moneo I, Mosquera D, Sáenz P, Masana L, Muñiz-Grijalvo O, Pérez-Calahorra S, Valdivielso P; Spanish Dyslipidemia Registry..

J Clin Lipidol. 2018 Nov - Dec;12(6):1482-1492.e3. doi: 10.1016/j.jacl.2018.07.013. Epub 2018 Aug 1.

PubMed [citation]

PMID:: 30150141

See all PubMed Citations (27)

Details of each submission

From GeneDx, SCV000617843.4

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

Description

Reported in the heterozygous state in association with hyperlipoproteinemia or hypertriglyceridemia (Chokshi et al., 2014; Johansen et al., 2014; Rodrigues et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 1522; ClinVar); Functional studies have demonstrated that G215E results in a complete loss of catalytic activity (Hata et al., 1992); This variant is associated with the following publications: (PMID: 28534127, 1619366, 1969408, 12905705, 18922999, 24793350, 24503134, 27055971, 24747307, 22095987, 24493316, 1975597, 1400331, 30150141, 29748148, 30210108, 32472350, 28438574, 29288010, 34426522, 31589614, 32041611, 33303402, 1351946)

#	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, SCV000935254.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 215 of the LPL protein (p.Gly215Glu). This variant is present in population databases (rs118204057, gnomAD 0.03%). This missense change has been observed in individuals with lipoprotein lipase deficiency (PMID: 1969408, 22095987, 28438574). This variant is also known as p.Gly188Glu. ClinVar contains an entry for this variant (Variation ID: 1522). 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) performed at Invitae indicates that this missense variant is not expected to disrupt LPL protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LPL function (PMID: 1400331, 1969408, 29288010). 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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001923354.1

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

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001959948.1

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

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002503124.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (21)

#	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		3	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003823435.2

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

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226795.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (15)

Description

PP1_strong, PM3, PS3, PS4_moderate

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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