NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 16, 2024
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:: RCV000791378.12

Allele description [Variation Report for NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)]

NM_000527.5(LDLR):c.1720C>T (p.Arg574Cys)

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.1720C>T (p.Arg574Cys)

Other names:

NM_000527.5(LDLR):c.1720C>T

HGVS:

NC_000019.10:g.11116873C>T
NG_009060.1:g.32493C>T
NM_000527.5:c.1720C>TMANE SELECT
NM_001195798.2:c.1720C>T
NM_001195799.2:c.1597C>T
NM_001195800.2:c.1216C>T
NM_001195803.2:c.1339C>T
NP_000518.1:p.Arg574Cys
NP_000518.1:p.Arg574Cys
NP_001182727.1:p.Arg574Cys
NP_001182728.1:p.Arg533Cys
NP_001182729.1:p.Arg406Cys
NP_001182732.1:p.Arg447Cys
LRG_274t1:c.1720C>T
LRG_274:g.32493C>T
NC_000019.9:g.11227549C>T
NM_000527.4(LDLR):c.1720C>T
NM_000527.4:c.1720C>T
P01130:p.Arg574Cys
c.1720C>T
p.(Arg574Cys)

Protein change:

R406C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000232; UniProtKB: P01130#VAR_072851; dbSNP: rs185098634

NCBI 1000 Genomes Browser:

rs185098634

Molecular consequence:

NM_000527.5:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1720C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1597C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1339C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

no known functional consequence - Comment(s)

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Ralstonia pickettii strain LMG6871 flagellin (fliC) gene, partial cds
Ralstonia pickettii strain LMG6871 flagellin (fliC) gene, partial cds
gi|28974938|gb|AY192718.1|

Nucleotide
BioAssays, RNAi Target, Active for Gene (Select 23043) (1)
PubChem BioAssay

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000752408	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11462246, 19446849, 20145306, 23375686, 25487149, 26892515, 20018285, 22698793, 28028493, 28492532
SCV001349170	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11462246, 15823288, 19318025, 19446849, 25647241, 26892515, 27050191, 30293936, 34297352, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000752408

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV001349170

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 5, 2023)

germline

clinical testing

PubMed (10)
[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

Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations.

Chmara M, Wasag B, Zuk M, Kubalska J, Wegrzyn A, Bednarska-Makaruk M, Pronicka E, Wehr H, Defesche JC, Rynkiewicz A, Limon J.

J Appl Genet. 2010;51(1):95-106. doi: 10.1007/BF03195716.

PubMed [citation]

PMID:: 20145306

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 (17)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000752408.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 574 of the LDLR protein (p.Arg574Cys). This variant is present in population databases (rs185098634, gnomAD 0.005%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11462246, 19446849, 20145306, 23375686, 25487149, 26892515). ClinVar contains an entry for this variant (Variation ID: 183123). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Arg574 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20018285, 22698793, 28028493). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

From Color Diagnostics, LLC DBA Color Health, SCV001349170.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces arginine with cysteine at codon 574 of the LDLR protein. This variant is also known as p.Arg553Cys in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 5 of the LDLR protein (a.a. 572-615), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A high-throughput experimental study has shown that this variant may not disrupt LDLR function (PMID: 25647241). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 11462246, 15823288, 19318025, 19446849, 26892515, 27050191, 30293936, 34297352). This variant has been stated to segregate with disease in a German family, although detailed data from the family study has not been provided (PMID: 11462246). This variant has been identified in 10/282878 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, p.Arg574His, is considered to be disease-causing (ClinVar variation ID: 251996), suggesting that arginine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Likely 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: Oct 20, 2024

ClinVar

Relating variation to medicine