NM_000527.5(LDLR):c.1694G>T (p.Gly565Val) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic/Likely pathogenic (8 submissions)
Last evaluated:: Nov 15, 2023
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:: RCV000003874.15

Allele description [Variation Report for NM_000527.5(LDLR):c.1694G>T (p.Gly565Val)]

NM_000527.5(LDLR):c.1694G>T (p.Gly565Val)

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.1694G>T (p.Gly565Val)

Other names:

G544V; FH Naples; FH Naples-2

HGVS:

NC_000019.10:g.11116201G>T
NG_009060.1:g.31821G>T
NM_000527.5:c.1694G>TMANE SELECT
NM_001195798.2:c.1694G>T
NM_001195799.2:c.1571G>T
NM_001195800.2:c.1190G>T
NM_001195803.2:c.1313G>T
NP_000518.1:p.Gly565Val
NP_000518.1:p.Gly565Val
NP_001182727.1:p.Gly565Val
NP_001182728.1:p.Gly524Val
NP_001182729.1:p.Gly397Val
NP_001182732.1:p.Gly438Val
LRG_274t1:c.1694G>T
LRG_274:g.31821G>T
LRG_274p1:p.Gly565Val
NC_000019.9:g.11226877G>T
NM_000527.4:c.1694G>T
P01130:p.Gly565Val
c.1694G>T
p.(Gly565Val)

Protein change:

G397V; GLY544VAL

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000424; UniProtKB: P01130#VAR_005401; OMIM: 606945.0014; dbSNP: rs28942082

Molecular consequence:

NM_000527.5:c.1694G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1694G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1571G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1190G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1313G>T - 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
SCV000024039	OMIM	no assertion criteria provided	Pathogenic (Sep 15, 1988)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000295584	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] 12436241, 2901412 Citation Link,
SCV000503387	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583865	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000599379	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 1301956
SCV000606487	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001653646	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 2901412, 23375686, 32770674, 25741868
SCV004825832	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Nov 15, 2023)	germline	clinical testing	PubMed (15) [See all records that cite these PMIDs] 1301956, 2901412, 6299582, 11313767, 12436241, 16257961, 16740646, 23375686, 27784735, 28161202, 32770674, 33994402, 34037665, 34297352, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	yes	14	4	not provided	2602	not provided	clinical testing, literature only
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing, research, curation
Caucasian	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Transport-deficient mutations in the low density lipoprotein receptor. Alterations in the cysteine-rich and cysteine-poor regions of the protein block intracellular transport.

Esser V, Russell DW.

J Biol Chem. 1988 Sep 15;263(26):13276-81.

PubMed [citation]

PMID:: 2901412

See all PubMed Citations (15)

Details of each submission

From OMIM, SCV000024039.1

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

Description

Esser and Russell (1988) found a GGC-to-GTC mutation as the basis of this variant.

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

From LDLR-LOVD, British Heart Foundation, SCV000295584.2

#	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 Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503387.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

Description

subjects mutated among 2600 FH index cases screened = 6 , family members = 2 with co-segregation / Functional test, FH-Naples-2, 2% LDLR Activity, Other mutations at same codon / Software predictions: Damaging

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		6	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583865.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	6	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		6	not provided	4	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599379.1

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

Description

"Assay Description:Hmz patients' fibroblasts, 125I-LDL assays"

PubMed [ID: 1301956]

#	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
2	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606487.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653646.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	2	not provided	not provided	clinical testing	PubMed (4)

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

From All of Us Research Program, National Institutes of Health, SCV004825832.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (15)

Description

The c.1694G>T (p.Gly565Val) variant in LDLR gene, that encodes for low density lipoprotein receptor, has been identified in at least five individuals who fulfill the clinical criteria of Familial Hypercholesterolemia (FH) (PMID:12436241, 23375686, 32770674, 28161202). This variant has also been reported in homozygous/compound heterozygous (with p.Trp4*) status in individuals with severe FH (PMID: 27784735, 6299582). This variant has also been detected in hypercholesterolemia cohorts and cohorts referred for FH testing (PMID: 34037665, 34297352). Experimental studies on transfected CHO cells demonstrated that this variant caused complete retention of protein on the endoplasmic reticulum, severely affected LDLR surface expression, and no LDL particle internalization (PMID: 16740646, 16257961). In addition, studies on homozygous mutant cells showed LDLR activity of <2% compared to wild type (PMID: 1301956, 2901412, 6299582). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.971). This variant is found to be absent in the general population database, gnomAD and interpreted as likely pathogenic/pathogenic by several submitters (10) in the ClinVar database (ClinVar ID: 3688). Other amino acid substitutions at the same codon (p.Gly565Arg, p.Gly565Asp, p.Gly565Ala) have been reported in individuals with FH (PMID: 33994402, 27784735, 11313767) and classified as likely pathogenic by ClinVar submitters (ClinVar ID: 1778186, 375819, 226366). Therefore, the c.1694G>T (p.Gly565Val) variant in LDLR gene is classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 12, 2026

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