rs113298164

chr15-58563549-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000236.3(LIPC):c.1214C>T(p.Thr405Met) variant causes a missense change. The variant allele was found at a frequency of 0.00255 in 1,614,152 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T405T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (17 hom.)
• Consequence: LIPC NM_000236.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5 B:3
• Conservation: PhyloP100: 7.18

Genes affected

LIPC (HGNC:6619): (lipase C, hepatic type) Enables phospholipase A1 activity and triglyceride lipase activity. Involved in several processes, including lipid homeostasis; plasma lipoprotein particle remodeling; and triglyceride catabolic process. Located in extracellular space. Implicated in several diseases, including Alzheimer's disease; coronary artery disease; familial combined hyperlipidemia; peripheral vascular disease; and type 2 diabetes mellitus. Biomarker of hyperinsulinism; obesity; and type 1 diabetes mellitus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015030295).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LIPC	NM_000236.3	c.1214C>T	p.Thr405Met	missense_variant	8/9	ENST00000299022.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LIPC	ENST00000299022.10	c.1214C>T	p.Thr405Met	missense_variant	8/9	1	NM_000236.3	P1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 432 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00293 AC: 737 AN: 251448 Hom.: 2 AF XY: 0.00274 AC XY: 372 AN XY: 135888

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0157

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00252 AC: 3682 AN: 1461860 Hom.: 17 Cov.: 32 AF XY: 0.00247 AC XY: 1794 AN XY: 727228

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74472

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.00360

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00266 Hom.: 4

Bravo AF: 0.00148

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000456 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00276 AC: 335

EpiCase AF: 0.00240

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	LIPC: BS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	This variant is associated with the following publications: (PMID: 32041611, 31589614, 31980526, 30333156, 28870971, 1671786, 24082139, 24497850, 20981092, 8732782, 1883393, 23685560, 8123642) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

Hyperlipidemia due to hepatic triglyceride lipase deficiency Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_000236.2:c.1214C>T in the LIPC gene has an allele frequency of 0.015 in European(Finnish) subpopulation in the gnomAD database.Functional studies demonstrate that p.Thr405Met has reduced enzymatic activity (PMID: 1883393). It was detected in multiple individuals with autosomal recessive Hepatic lipase deficiency, compound heterozygous with c.1214C>T (p.Thr405Met) (PMID: 1883393).The patient's phenotype is highly specific for LIPC gene (PMID: 1671786). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PS3; PM3; PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Type 2 diabetes mellitus Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 24, 2020

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Thr405Met variant in LIPC (also reported as p.Thr383Met in the literature) has been identified in the compound heterozygous state in at least 2 individuals with hepatic lipase deficiency and segregated with disease in 5 affected relatives from 2 families (Hegele 1991 PMID: 1883393, Hegele 1991 PMID: 1671786, Ruel 2003 PMID: 12777476 ). This variant has also been identified in the heterozygous state in 3 individuals with biochemical features consistent with hepatic lipase deficiency (Knudsen 1996 PMID: 8732782, Motazacker 2013 PMID: 23685560, Geller 2018 PMID: 30333156). Additionally, this variant has been reported in ClinVar (Variation ID # 14451) and has been identified in 1.5% (388/25112) of Finnish chromosomes, including 3 homozygotes, and 0.3% (460/129166) of European chromosomes, including 2 homozygotes, by gnomAD (http://gnomad.broadinstitute.org). In vitro functional studies provide some evidence that this variant impacts protein function (Knudsen 1996 PMID: 8732782, Durstenfeld 1994 PMID: 8123642); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain as it is unclear what clinical effect of the biochemical change in lipid levels has on people with hepatic lipase deficiency, particularly on how they affect the risk of atherosclerosis in some individuals and not in others and whether that risk is greater than individuals in the general population (Brunzell 2011 PMID: 21986251, Kobayashi 2015 PMID: 25995285). ACMG/AMP Criteria applied:PP1_Strong, PM3, PS3_Supporting. -

Type 1 diabetes mellitus 2;C2675071:High density lipoprotein cholesterol level quantitative trait locus 12;C3151466:Hyperlipidemia due to hepatic triglyceride lipase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Feb 24, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.019	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D;.;D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Uncertain	-0.0078	T
MutationAssessor	Pathogenic	3.1	M;.;M;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Uncertain	0.45
Sift	Benign	0.043	D;T;D;T
Sift4G	Benign	0.16	T;T;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.76
MVP		0.85
MPC		0.43
ClinPred		0.040	T
GERP RS		5.9
Varity_R		0.17
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113298164; hg19: chr15-58855748;