NM_000527.5(LDLR):c.1694G>T (p.Gly565Val) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 9, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001195593.4

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:: Homozygous familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001365989	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Jan 9, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 2901412, 12436241, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001365989

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Jan 9, 2020)

germline

clinical testing

PubMed (3)
[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	2	2	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia.

Amsellem S, Briffaut D, Carrié A, Rabès JP, Girardet JP, Fredenrich A, Moulin P, Krempf M, Reznik Y, Vialettes B, de Gennes JL, Brukert E, Benlian P.

Hum Genet. 2002 Dec;111(6):501-10. Epub 2002 Sep 13.

PubMed [citation]

PMID:: 12436241

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV001365989.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

Description

The p.Gly565Val variant in LDLR (also described as p.Gly544Val in the literature) has been reported in the heterozygous state in at least 5 individuals and in the homozygous state in 1 individual with familial hypercholesterolemia (FH) and segregated with disease in 2 affected relatives from at least one family (ClinVar: SCV000503387.1 and SCV000583865.1, Esser 1988, Amsellem 2002). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 3688) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies support an impact on protein function (Esser 1988). Additional variants involving this codon (p.Gly565Asp and p.Gly565Ala) have been identified in individuals with FH. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting

#	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		2	not provided	2	not provided

Last Updated: Apr 12, 2026

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