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

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 18, 2025
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:: RCV000791454.9

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]

Condition(s)

Name:: Familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemias; 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
SCV000752407	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 18, 2025)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 12436241, 23375686, 2901412, 16740646, 11313767, 27784735, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752407

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 18, 2025)

germline

clinical testing

PubMed (7)
[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

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

Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy.

Bertolini S, Pisciotta L, Rabacchi C, Cefalù AB, Noto D, Fasano T, Signori A, Fresa R, Averna M, Calandra S.

Atherosclerosis. 2013 Apr;227(2):342-8. doi: 10.1016/j.atherosclerosis.2013.01.007. Epub 2013 Jan 19.

PubMed [citation]

PMID:: 23375686

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752407.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 565 of the LDLR protein (p.Gly565Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 2901412, 12436241, 23375686). 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 pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 377,766 individuals referred to our laboratory for LDLR testing. ClinVar contains an entry for this variant (Variation ID: 3688). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 2901412, 16740646). This variant disrupts the p.Gly565 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 11313767, 27784735), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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: Apr 12, 2026

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