NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 19, 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:: RCV000775061.10

Allele description [Variation Report for NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)]

NM_000527.5(LDLR):c.1241T>G (p.Leu414Arg)

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.1241T>G (p.Leu414Arg)

Other names:

NP_000518.1:p.L414R; NM_000527.5(LDLR):c.1241T>G

HGVS:

NC_000019.10:g.11113332T>G
NG_009060.1:g.28952T>G
NM_000527.5:c.1241T>GMANE SELECT
NM_001195798.2:c.1241T>G
NM_001195799.2:c.1118T>G
NM_001195800.2:c.737T>G
NM_001195803.2:c.860T>G
NP_000518.1:p.Leu414Arg
NP_000518.1:p.Leu414Arg
NP_001182727.1:p.Leu414Arg
NP_001182728.1:p.Leu373Arg
NP_001182729.1:p.Leu246Arg
NP_001182732.1:p.Leu287Arg
LRG_274t1:c.1241T>G
LRG_274:g.28952T>G
LRG_274p1:p.Leu414Arg
NC_000019.9:g.11224008T>G
NM_000527.4:c.1241T>G
P01130:p.Leu414Arg
c.1241T>G

Protein change:

L246R

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000372; UniProtKB: P01130#VAR_005379; dbSNP: rs748554592

NCBI 1000 Genomes Browser:

rs748554592

Molecular consequence:

NM_000527.5:c.1241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1118T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.737T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.860T>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
SCV000909162	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001360702	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 8, 2019)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 18022922, 29353225, 30592178, 28502495, 9452118 Citation Link,
SCV001575511	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9452118, 27765764, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909162

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2019)

germline

clinical testing

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

SCV001360702

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 8, 2019)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001575511

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 19, 2023)

germline

clinical testing

PubMed (3)
[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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Genetic analysis of Indian subjects with clinical features of possible type IIa hypercholesterolemia.

Kondkar AA, Nair KG, Ashavaid TF.

J Clin Lab Anal. 2007;21(6):375-81.

PubMed [citation]

PMID:: 18022922
PMCID:: PMC6649063

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909162.3

#	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.Leu393Arg in the mature protein) replaces leucine with arginine at codon 414 in the first EGF-like repeat B in the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 26608663, 26875521, 27765764, 29353225, 9763532). This variant has been identified in 2/251172 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360702.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: LDLR c.1241T>G (p.Leu414Arg) results in a non-conservative amino acid change in 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 251172 control chromosomes. c.1241T>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Mak_1998, Kondkar_2007, Chiou_2017, Chan_2018, Pek_2018), predominantly in individuals from Asian origin. 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. Two ClinVar submissions (evaluation after 2014) cite variant as 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001575511.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 414 of the LDLR protein (p.Leu414Arg). This variant is present in population databases (rs748554592, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9452118, 27765764). This variant is also known as L393R. ClinVar contains an entry for this variant (Variation ID: 251747). 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

Last Updated: Nov 3, 2024

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