NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 24, 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:: RCV000589820.14

Allele description [Variation Report for NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)]

NM_000527.5(LDLR):c.2096C>T (p.Pro699Leu)

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.2096C>T (p.Pro699Leu)

Other names:

NP_000518.1:p.P699L; NM_000527.5(LDLR):c.2096C>T

HGVS:

NC_000019.10:g.11120478C>T
NG_009060.1:g.36098C>T
NM_000527.5:c.2096C>TMANE SELECT
NM_001195798.2:c.2096C>T
NM_001195799.2:c.1973C>T
NM_001195800.2:c.1592C>T
NM_001195803.2:c.1606+245C>T
NP_000518.1:p.Pro699Leu
NP_000518.1:p.Pro699Leu
NP_001182727.1:p.Pro699Leu
NP_001182728.1:p.Pro658Leu
NP_001182729.1:p.Pro531Leu
LRG_274t1:c.2096C>T
LRG_274:g.36098C>T
LRG_274p1:p.Pro699Leu
NC_000019.9:g.11231154C>T
NM_000527.4:c.2096C>T
P01130:p.Pro699Leu
c.2096C>T

Protein change:

P531L

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001600; UniProtKB: P01130#VAR_013955

Molecular consequence:

NM_001195803.2:c.1606+245C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2096C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1973C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1592C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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protein unc-80 homolog isoform X12 [Rattus norvegicus]
protein unc-80 homolog isoform X12 [Rattus norvegicus]
gi|1958805107|ref|XP_038940529.1|

Protein
NADH dehydrogenase subunit 6 (mitochondrion) [Apterichtus klazingai]
NADH dehydrogenase subunit 6 (mitochondrion) [Apterichtus klazingai]
gi|2580280160|gb|WNH21308.1|

Protein
Chromosome neighbors for GEO Profiles (Select 77148430) (20)
GEO Profiles
BioAssays, Active for PubChem Compound (Select 91623361) (0)
PubChem BioAssay
Protein Links for Conserved Domains (Select 236686) (4300)
Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000544654	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7489239, 10882754, 21310417, 21642693, 22390909, 23375686, 25461735, 26892515, 27765764, 28492532
SCV000697211	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Sep 21, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23064986, 23375686, 22698793, 25461735, 26892515, 22390909, 34456049, 7489239 Citation Link,
SCV000911498	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 3, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 10882754, 11810272, 11851376, 19318025, 20089850, 21310417, 21642693, 22698793, 23064986, 23375686, 26892515, 27824480, 33994402, 34037665, 35137788, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000544654

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 24, 2024)

germline

clinical testing

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

SCV000697211

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Sep 21, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV000911498

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 3, 2023)

germline

clinical testing

PubMed (16)
[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

Polygenic Versus Monogenic Causes of Hypercholesterolemia Ascertained Clinically.

Wang J, Dron JS, Ban MR, Robinson JF, McIntyre AD, Alazzam M, Zhao PJ, Dilliott AA, Cao H, Huff MW, Rhainds D, Low-Kam C, Dubé MP, Lettre G, Tardif JC, Hegele RA.

Arterioscler Thromb Vasc Biol. 2016 Dec;36(12):2439-2445. Epub 2016 Oct 20.

PubMed [citation]

PMID:: 27765764

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

See all PubMed Citations (22)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000544654.9

#	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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 699 of the LDLR protein (p.Pro699Leu). This variant is present in population databases (rs201573863, gnomAD 0.04%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7489239, 10882754, 21310417, 21642693, 22390909, 23375686, 25461735, 26892515, 27765764). This variant is also known as Pro678Leu. ClinVar contains an entry for this variant (Variation ID: 252219). 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%. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697211.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: LDLR c.2096C>T (p.Pro699Leu) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) 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 2e-05 in 251028 control chromosomes. c.2096C>T has been reported in the literature as a heterozygous genotype in multiple individuals affected with autosomal dominant Familial Hypercholesterolemia (example, Schuster_1995, Huijgen_2012, Bertolini_2013, Jannes_2015, Wang_2016, Tichy_2012, Ahmad_2012, Marco-Benedi_2022, Sharifi_2016) to include at-least one compound heterozygous proband with severe Hypercholesterolemia whose obligate carrier father with this variant was reportedly unaffected, i.e., normal cholesterol levels at age 39 (Schuster_1995). This same study also reported co-segregation with Hypercholesterolemia in a second family but did not provide primary evidence supporting this finding (Schuster_1995). As the variant allele was transmitted much more often than the reference allele to affected members in tested families, these data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 23064986, 23375686, 22698793, 22390909, 25461735, Wang_2016 has NO_PMID, 7489239, 34456049, 26892515). Multiple submitters including an expert panel (ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel) have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments but a predominant consensus as Pathogenic/Likely pathogenic (n=12) and VUS (n=4 to include the Expert Panel). Some submitters cite overlapping evidence utilized in the context of this evaluation while the Expert Panel cites both apparent non-segregation and co-segregation without providing primary evidence for independent corroboration. 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

From Color Diagnostics, LLC DBA Color Health, SCV000911498.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant replaces proline with leucine at codon 699 in the EGF-like repeat C of the EGF precursor homology domain of the LDLR protein. This variant is also known as p.Pro678Leu in the mature protein. 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 using transfected HeLa cells has shown that this variant causes LDLR protein misfolding and retention in the endoplasmic reticulum (PMID: 20089850). This variant has been reported in over 20 individuals affected with familial hypercholesterolemia (PMID: 10882754, 11810272, 11851376, 19318025, 21310417, 21642693, 22698793, 23064986, 23375686, 26892515, 27824480, 33994402, 34037665, 35137788). While this variant has been shown to segregate with disease, with 58 informative meioses across 9 families, it has also shown non-segregation in 11 informative meioses across 6 families (ClinVar SCV001960938.1). This variant has been identified in 11/282422 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

Last Updated: Oct 13, 2024

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