NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 27, 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:: RCV000775072.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)]

NM_000527.5(LDLR):c.1576C>T (p.Pro526Ser)

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.1576C>T (p.Pro526Ser)

Other names:

FH Cincinnati-3; NM_000527.5(LDLR):c.1576C>T

HGVS:

NC_000019.10:g.11113752C>T
NG_009060.1:g.29372C>T
NM_000527.5:c.1576C>TMANE SELECT
NM_001195798.2:c.1576C>T
NM_001195799.2:c.1453C>T
NM_001195800.2:c.1072C>T
NM_001195803.2:c.1195C>T
NP_000518.1:p.Pro526Ser
NP_000518.1:p.Pro526Ser
NP_001182727.1:p.Pro526Ser
NP_001182728.1:p.Pro485Ser
NP_001182729.1:p.Pro358Ser
NP_001182732.1:p.Pro399Ser
LRG_274t1:c.1576C>T
LRG_274:g.29372C>T
LRG_274p1:p.Pro526Ser
NC_000019.9:g.11224428C>T
NM_000527.4:c.1576C>T
P01130:p.Pro526Ser
c.1576C>T

Protein change:

P358S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000076; UniProtKB: P01130#VAR_005396; dbSNP: rs730882106

NCBI 1000 Genomes Browser:

rs730882106

Molecular consequence:

NM_000527.5:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1576C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1453C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1072C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1195C>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536] - Comment(s)

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
SCV000627019	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 27, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9259195, 11462246, 27497240, 1301956, 25647241, 28492532
SCV000909174	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1301956, 9259195, 10208479, 11462246, 25647241, 27497240, 31345425, 34037665, 25741868
SCV002522192	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627019

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 27, 2024)

germline

clinical testing

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

SCV000909174

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 18, 2023)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV002522192

National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 6, 2021)

germline

clinical testing

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

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
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

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

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627019.6

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

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 526 of the LDLR protein (p.Pro526Ser). This variant is present in population databases (rs730882106, gnomAD 0.002%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 1301956, 9259195, 11462246, 27497240; Invitae). This variant is also known as p.Pro505Ser. ClinVar contains an entry for this variant (Variation ID: 183120). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 1301956, 25647241). 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, SCV000909174.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This missense variant replaces proline with serine at codon 526 in the third LDLR type B repeat of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro505Ser in the mature protein; FH Cincinnati-3. 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 functional study has shown that this variant interferes with protein transport and significantly affects LDLR biosynthesis or turnover (PMID: 25647241). Another functional study has shown significantly reduced LDLR activity (5-15% of the wild type) in cells from an individual with heterozygous hypercholesterolemia (PMID: 1301956). This variant has been reported in over 10 individuals affected with familial hypercholesterolemia (PMID: 1301956, 9259195, 10208479, 11462246, 27497240, 31345425, 34037665; Color internal data). This variant has been identified in 3/282624 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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

From National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health, SCV002522192.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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