NM_000527.5(LDLR):c.519C>G (p.Cys173Trp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 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:: RCV000791359.11

Allele description [Variation Report for NM_000527.5(LDLR):c.519C>G (p.Cys173Trp)]

NM_000527.5(LDLR):c.519C>G (p.Cys173Trp)

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.519C>G (p.Cys173Trp)

Other names:

NP_000518.1:p.C173W

HGVS:

NC_000019.10:g.11105425C>G
NG_009060.1:g.21045C>G
NM_000527.5:c.519C>GMANE SELECT
NM_001195798.2:c.519C>G
NM_001195799.2:c.396C>G
NM_001195800.2:c.314-1967C>G
NM_001195803.2:c.314-1140C>G
NP_000518.1:p.Cys173Trp
NP_000518.1:p.Cys173Trp
NP_001182727.1:p.Cys173Trp
NP_001182728.1:p.Cys132Trp
LRG_274t1:c.519C>G
LRG_274:g.21045C>G
LRG_274p1:p.Cys173Trp
NC_000019.9:g.11216101C>G
NM_000527.4:c.519C>G
P01130:p.Cys173Trp
c.519C>G

Protein change:

C132W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000391; UniProtKB: P01130#VAR_005325; dbSNP: rs769318035

NCBI 1000 Genomes Browser:

rs769318035

Molecular consequence:

NM_001195800.2:c.314-1967C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1140C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.519C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.519C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.396C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV000544646	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9452094, 11462246, 11810272, 25962062, 7489239, 20019594, 28492532
SCV001736423	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 4, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001983507	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 8, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11462246, 9544726, 9452094, 16502360, 11810272, 10090484 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544646

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 15, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV001736423

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 4, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001983507

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 8, 2021)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

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

Genetic testing of Korean familial hypercholesterolemia using whole-exome sequencing.

Han SM, Hwang B, Park TG, Kim DI, Rhee MY, Lee BK, Ahn YK, Cho BR, Woo J, Hur SH, Jeong JO, Park S, Jang Y, Lee MG, Bang D, Lee JH, Lee SH.

PLoS One. 2015;10(5):e0126706. doi: 10.1371/journal.pone.0126706.

PubMed [citation]

PMID:: 25962062
PMCID:: PMC4427254

Ten LDL receptor mutants explain one third of familial hypercholesterolemia in a German sample.

Schuster H, Keller C, Wolfram G, Zöllner N.

Arterioscler Thromb Vasc Biol. 1995 Dec;15(12):2176-80.

PubMed [citation]

PMID:: 7489239

See all PubMed Citations (11)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544646.7

#	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 cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the LDLR protein (p.Cys173Trp). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9452094, 11462246, 11810272, 25962062). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys152Trp. ClinVar contains an entry for this variant (Variation ID: 251277). 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.Cys173 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7489239, 20019594). 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, SCV001736423.1

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

Description

This missense variant (also known as p.Cys152Trp in the mature protein) replaces cysteine with tryptophan at codon 173 in the LDLR type A repeat 4 in the ligand binding domain of the LDLR protein. This variant alters one of the highly conserved cysteine residues that are critical for proper protein folding and function (PMID: 2088165, 6091915, 15952897). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant results in a significant decrease in LDL binding and internalization (PMID: 9544726, 16502360). This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 11462246, 11810272, 25962062, 31345425, 32044282, 32220565) and has been shown to segregate with hypercholesterolemia in over ten individuals from two unrelated families (PMID: 9452094, 9544726). This variant has been identified in 2/251308 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001983507.1

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

Description

Variant summary: LDLR c.519C>G (p.Cys173Trp) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251308 control chromosomes (gnomAD). c.519C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and has been shown to segregate with disease in several affected individuals within two unrelated families (e.g. Couture_1998, Morash_1998, Ebhardt_1999, Fouchier_2001, Nauck_2001, Plewa_2006). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant results in a significant decrease in LDL binding capacity (Morash_1998, Plewa_2006). Eight ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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: Sep 29, 2024

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