NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Aug 26, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000238445.11

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]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295964	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 19318025, 19446849 Citation Link,
SCV000607695	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV002764284	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Jun 4, 2021)	germline	clinical testing	Citation Link,
SCV002817152	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Aug 26, 2022)	germline	curation	Citation Link,
SCV003816532	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820676	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Aug 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19318025, 19446849, 23375686, 32719484, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only
not provided	germline	unknown	15	not provided	not provided	143476	not provided	clinical testing, research, curation

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

The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia.

Guardamagna O, Restagno G, Rolfo E, Pederiva C, Martini S, Abello F, Baracco V, Pisciotta L, Pino E, Calandra S, Bertolini S.

J Pediatr. 2009 Aug;155(2):199-204.e2. doi: 10.1016/j.jpeds.2009.02.022. Epub 2009 May 15.

PubMed [citation]

PMID:: 19446849

See all PubMed Citations (5)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607695.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

%MAF(ExAC):0.006595

#	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 New York Genome Center, SCV002764284.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is found with low frequency in gnomAD(v2.1.1)(29 heterozygotes, 0 homozygotes; allele frequency: 1.03e-4), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.024) and Pathogenic (REVEL; score:0.773) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance as well as Likely Pathogenic (VarID:252295), and has been reported in individuals with hypercholesterolemia [PMID:19446849, 18096825, 19318025, 23375686], and has also been identified in healthy unaffected individuals [PMID:32719484]. The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817152.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PP3: REVEL = 0.773. PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1). PP4, PS4 not applicable: Variant did not meet PM2. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.

#	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 Revvity Omics, Revvity, SCV003816532.3

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

From All of Us Research Program, National Institutes of Health, SCV004820676.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	14	not provided	not provided	clinical testing	PubMed (5)

Description

This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). 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), as well as in healthy individuals (PMID: 32719484). 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	143475	not provided	not provided		14	not provided	not provided	not provided

Last Updated: Sep 27, 2025

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