VCV000003660.7 - ClinVar

NM_000229.2(LCAT):c.440C>T (p.Thr147Ile)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (2)

2 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000229.2(LCAT):c.440C>T (p.Thr147Ile)

Variation ID: 3660 Accession: VCV000003660.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q22.1 16: 67942754 (GRCh38) [ NCBI UCSC ] 16: 67976657 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 27, 2015	Feb 23, 2026	Sep 17, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_000229.2:c.440C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000220.1:p.Thr147Ile	missense
NM_000229.1:c.440C>T
NC_000016.10:g.67942754G>A
NC_000016.9:g.67976657G>A
NG_009778.1:g.6359C>T
NG_033098.1:g.30941C>T
	P04180:p.Thr147Ile

... more HGVS ... less HGVS

Protein change

T147I

Other names

I123T

Canonical SPDI

NC_000016.10:67942753:G:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00004

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00004

Links

UniProtKB: P04180#VAR_004256 OMIM: 606967.0005 dbSNP: rs121908050 ClinGen: CA116418 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
LCAT		-	-	GRCh38 GRCh37	298	390

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Fish-eye disease	Pathogenic (1)	no assertion criteria provided	Feb 1, 1992	RCV000003845.4
Fish-eye disease Norum disease	Pathogenic (1)	criteria provided, single submitter	Apr 4, 2022	RCV002504739.1
not provided	Pathogenic (1)	criteria provided, single submitter	Sep 17, 2025	RCV003555908.4
LCAT-related disorder	Likely pathogenic (1)	no assertion criteria provided	Apr 7, 2024	RCV004754238.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Fish-eye disease Norum disease	Fulgent Genetics, Fulgent Genetics Accession: SCV002808743.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Sep 17, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV004297019.3 First in ClinVar: Feb 14, 2024 Last updated: Feb 23, 2026	Publications: PubMed (4) PubMed: 1588268‚ 2052566‚ 21901787‚ 25948084 Comment: show 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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LCAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LCAT function (PMID: 25948084). For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 07, 2024) N Not contributing to aggregate classification	no assertion criteria provided	LCAT-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005347106.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 01, 1992) N Not contributing to aggregate classification	no assertion criteria provided	FISH-EYE DISEASE	OMIM Accession: SCV000024010.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 17, 2019	Publications: PubMed (2) PubMed: 1737840‚ 2052566 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: Funke et al. (1991) described the biochemical and genetic presentation of 2 homozygotes from a German family with fish-eye disease (136120) and their relatives. They … (more) Funke et al. (1991) described the biochemical and genetic presentation of 2 homozygotes from a German family with fish-eye disease (136120) and their relatives. They demonstrated vertical transmission of a decrease in the specific activity of LCAT. Two brothers, 57 and 68 years old, had massive bilateral corneal opacities that almost completely covered the irides. There were several consanguineous marriages in their family history. In their village, the kindred was known to have been affected with 'sick eyes' for several generations. The younger brother suffered from angiographically assessed 2-vessel coronary disease. The elder brother suffered from angina pectoris. Family history, however, was not compatible with an increased prevalence of myocardial infarction. All 5 children of the 2 presumed homozygotes were heterozygotes. Direct sequencing of DNA segments of the LCAT gene amplified by PCR led to the identification of a homozygous mutation resulting in the substitution of isoleucine for threonine at codon 123 (T123I). The change was from ACA to ATA. Homozygosity for precisely the same mutation was identified in an unrelated Dutch family. In a 66-year-old patient with fish-eye disease, Klein et al. (1992) found compound heterozygous mutations in the LCAT gene: T123I and thr347-to-met (T347M; 606967.0009). (less)

Comment:

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt LCAT protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LCAT function (PMID: 25948084). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
The Effect of Natural LCAT Mutations on the Biogenesis of HDL.	Fotakis P	Biochemistry	2015	PMID: 25948084
High prevalence of mutations in LCAT in patients with low HDL cholesterol levels in The Netherlands: identification and characterization of eight novel mutations.	Holleboom AG	Human mutation	2011	PMID: 21901787
Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123----Ile) and lecithin-cholesterol acyltransferase (Thr347----Met).	Klein HG	The Journal of clinical investigation	1992	PMID: 1737840
Familial high-density-lipoprotein deficiency causing corneal opacities (fish eye disease) in a family of Dutch descent.	Kastelein JJ	Journal of internal medicine	1992	PMID: 1588268
A molecular defect causing fish eye disease: an amino acid exchange in lecithin-cholesterol acyltransferase (LCAT) leads to the selective loss of alpha-LCAT activity.	Funke H	Proceedings of the National Academy of Sciences of the United States of America	1991	PMID: 2052566

Text-mined citations for rs121908050 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Mar 01, 2026