NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 16, 2025
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:: RCV001523921.9

Allele description [Variation Report for NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)]

NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)

Other names:

NM_000527.5(LDLR):c.2375T>C; p.Ile792Thr

HGVS:

NC_000019.10:g.11128071T>C
NG_009060.1:g.43691T>C
NM_000527.5:c.2375T>CMANE SELECT
NM_001195798.2:c.2375T>C
NM_001195799.2:c.2252T>C
NM_001195800.2:c.1871T>C
NM_001195803.2:c.1841T>C
NP_000518.1:p.Ile792Thr
NP_000518.1:p.Ile792Thr
NP_001182727.1:p.Ile792Thr
NP_001182728.1:p.Ile751Thr
NP_001182729.1:p.Ile624Thr
NP_001182732.1:p.Ile614Thr
LRG_274t1:c.2375T>C
LRG_274:g.43691T>C
LRG_274p1:p.Ile792Thr
NC_000019.9:g.11238747T>C
NM_000527.4:c.2375T>C
c.2375T>C

Protein change:

I614T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001635; dbSNP: rs764493597

NCBI 1000 Genomes Browser:

rs764493597

Molecular consequence:

NM_000527.5:c.2375T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2375T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2252T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1871T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1841T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Synonyms:: Familial hypercholesterolaemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001733661	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 24, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19318025, 19446849, 23375686, 30293936, 25741868
SCV002086876	Natera, Inc.	no assertion criteria provided	Uncertain significance (Jan 14, 2020)	germline	clinical testing
SCV003269197	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 16, 2025)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 18096825, 19446849, 23375686, 34456049, 35913489, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001733661

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jun 24, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002086876

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Jan 14, 2020)

germline

clinical testing

SCV003269197

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 16, 2025)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

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

Citations

PubMed

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

Autosomal dominant hypercholesterolemia in Catalonia: Correspondence between clinical-biochemical and genetic diagnostics in 967 patients studied in a multicenter clinical setting.

Martín-Campos JM, Plana N, Figueras R, Ibarretxe D, Caixàs A, Esteve E, Pérez A, Bueno M, Mauri M, Roig R, Martínez S, Pintó X, Masana L, Julve J, Blanco-Vaca F; Xarxa d’Unitats de Lípids i Arteriosclerosi (XULA).

J Clin Lipidol. 2018 Nov-Dec;12(6):1452-1462. doi: 10.1016/j.jacl.2018.09.002. Epub 2018 Sep 7.

PubMed [citation]

PMID:: 30293936

See all PubMed Citations (9)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001733661.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant replaces isoleucine with threonine at codon 792 of the LDLR protein. This variant is also known as p.Ile771Thr in the mature protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686, 30293936). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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., SCV002086876.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003269197.3

#	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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). This variant is present in population databases (rs764493597, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 18096825, 19446849, 23375686, 34456049, 35913489). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be benign with a negative predictive value of at least 95%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 252295). 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 LDLR protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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

Last Updated: Sep 27, 2025

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