rs121908050

Positions:

chr16-67942754-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The ENST00000264005.10(LCAT):c.440C>T(p.Thr147Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,612,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000064 ( 0 hom. )

Consequence

LCAT
ENST00000264005.10 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 5.80

Variant links:

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

LCAT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 16-67942754-G-A is Pathogenic according to our data. Variant chr16-67942754-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3660.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67942754-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCAT	NM_000229.2 linkuse as main transcript	c.440C>T	p.Thr147Ile	missense_variant	4/6	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10 linkuse as main transcript	c.440C>T	p.Thr147Ile	missense_variant	4/6	1	NM_000229.2	ENSP00000264005	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000441

AC:

AN:

249582

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000978

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000644

AC:

AN:

1460546

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

726580

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000836

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000938

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 147 of the LCAT protein (p.Thr147Ile). This variant is present in population databases (rs121908050, gnomAD 0.009%). This missense change has been observed in individual(s) with Fish-eye disease (PMID: 1588268, 2052566, 21901787). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr123Ile. ClinVar contains an entry for this variant (Variation ID: 3660). 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 LCAT protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LCAT function (PMID: 25948084). For these reasons, this variant has been classified as Pathogenic. -

LCAT-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 07, 2024

The LCAT c.440C>T variant is predicted to result in the amino acid substitution p.Thr147Ile. This variant, also described as p.Thr123Ile using legacy nomenclature, has been reported in the compound heterozygous and homozygous states in multiple individuals with partial lecithin-cholesterol acyltransferase deficiency (Funke et al. 1991. PubMed ID: 2052566; Kastelein et al. 1992. PubMed ID: 1588268; Klein et al. 1992. PubMed ID: 1737840; Holleboom et al. 2011. PubMed ID: 21901787; Ono et al. 2020. PubMed ID: 33324778) and has been observed to co-segregate with disease in two large families (Funke et al. 1991. PubMed ID: 2052566; Kastelein et al. 1992. PubMed ID: 1588268). In vitro and in vivo functional studies have demonstrated that this variant renders LCAT unable to bind cholesterol to HDL (α-LCAT activity) while retaining activity toward VLDL and LDL (β-LCAT activity) (Holleboom et al. 2011. PubMed ID: 21901787; Fotakis et al. 2015. PubMed ID: 25948084). This variant is reported in 0.0098% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Fish-eye disease

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 1992

- -

Norum disease;C0342895:Fish-eye disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

D;D

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.1

M;.

MutationTaster

Benign

0.91

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.6

D;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;.

Vest4

0.95

MVP

0.99

MPC

0.90

ClinPred

0.90

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over