NM_000237.3(LPL):c.998G>A (p.Arg333His) AND Hyperlipoproteinemia, type I

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: May 19, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000778928.10

Allele description [Variation Report for NM_000237.3(LPL):c.998G>A (p.Arg333His)]

NM_000237.3(LPL):c.998G>A (p.Arg333His)

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.998G>A (p.Arg333His)

Other names:

p.Arg333His

HGVS:

NC_000008.11:g.19956063G>A
NG_008855.2:g.59347G>A
NM_000237.3:c.998G>AMANE SELECT
NP_000228.1:p.Arg333His
LRG_1298t1:c.998G>A
LRG_1298:g.59347G>A
LRG_1298p1:p.Arg333His
NC_000008.10:g.19813574G>A
NC_000008.10:g.19813574G>A
NG_008855.1:g.21993G>A
NM_000237.2:c.998G>A

Protein change:

R333H

Links:

dbSNP: rs144466625

NCBI 1000 Genomes Browser:

rs144466625

Molecular consequence:

NM_000237.3:c.998G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hyperlipoproteinemia, type I
Synonyms:: HYPERLIPOPROTEINEMIA, TYPE IA; Lipase D deficiency; Hyperlipoproteinemia type 1; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009387; MedGen: C0023817; Orphanet: 444490; OMIM: 238600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915343	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Uncertain significance (Oct 24, 2017)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24291057, 27055971, 28606150, 25966443 Citation Link,
SCV002083222	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Jul 24, 2020)	germline	clinical testing
SCV002547913	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 26, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25966443, 27055971, 24291057 Citation Link,
SCV004041255	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 19, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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

Severe hypertriglyceridemia in Norway: prevalence, clinical and genetic characteristics.

Retterstøl K, Narverud I, Selmer R, Berge KE, Osnes IV, Ulven SM, Halvorsen B, Aukrust P, Holven KB, Iversen PO.

Lipids Health Dis. 2017 Jun 12;16(1):115. doi: 10.1186/s12944-017-0511-9.

PubMed [citation]

PMID:: 28606150
PMCID:: PMC5469061

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

See all PubMed Citations (5)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000915343.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The LPL c.998G>A (p.Arg333His) variant has been reported in four studies in which it is found in at least three individuals affected with lipoprotein lipase deficiency, including in one in a compound heterozygous state with a second missense variant known to result in complete loss of LPL function and in two in a heterozygous state (MartÃn-Campos et al. 2014; Rabacchi et al. 2015; Rodrigues et al. 2016; RetterstÃ¸l et al. 2017). The p.Arg333His variant was absent from 250 control individuals and is reported at a frequency of 0.00067 in the African population of the Genome Aggregation Database. Expression of the p.Arg333His variant in COS-1 cells revealed that postheparin lipoprotein lipase activity was 6% of wild type levels (MartÃn-Campos et al. 2014). Based on the evidence, the p.Arg333His variant is classified as a variant of unknown significance but suspicious for pathogenicity for familial lipoprotein lipase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Natera, Inc., SCV002083222.1

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002547913.1

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

Description

Variant summary: LPL c.998G>A (p.Arg333His) results in a non-conservative amino acid change located in the Lipase domain (IPR013818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251294 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in LPL causing Familial Lipoprotein Lipase Deficiency (4.8e-05 vs 0.0034), allowing no conclusion about variant significance. c.998G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Lipoprotein Lipase Deficiency (example, Martin-Campos_2014). At least one publication reports experimental evidence evaluating an impact on protein function (Martin-Campos_2014). The most pronounced variant effect results in <10% of normal lipoprotein lipase enzyme activity in vitro. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely pathogenic, n=2; VUS, n=2). Based on the evidence outlined above, the variant was 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

From Baylor Genetics, SCV004041255.1

#	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

Last Updated: Nov 24, 2024

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