NM_000527.5(LDLR):c.1367T>C (p.Leu456Pro) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 16, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000775067.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1367T>C (p.Leu456Pro)]

NM_000527.5(LDLR):c.1367T>C (p.Leu456Pro)

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.1367T>C (p.Leu456Pro)

HGVS:

NC_000019.10:g.11113543T>C
NG_009060.1:g.29163T>C
NM_000527.5:c.1367T>CMANE SELECT
NM_001195798.2:c.1367T>C
NM_001195799.2:c.1244T>C
NM_001195800.2:c.863T>C
NM_001195803.2:c.986T>C
NP_000518.1:p.Leu456Pro
NP_000518.1:p.Leu456Pro
NP_001182727.1:p.Leu456Pro
NP_001182728.1:p.Leu415Pro
NP_001182729.1:p.Leu288Pro
NP_001182732.1:p.Leu329Pro
LRG_274t1:c.1367T>C
LRG_274:g.29163T>C
LRG_274p1:p.Leu456Pro
NC_000019.9:g.11224219T>C
NM_000527.4:c.1367T>C

Protein change:

L288P

Links:

dbSNP: rs200143634

NCBI 1000 Genomes Browser:

rs200143634

Molecular consequence:

NM_000527.5:c.1367T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1367T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1244T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.863T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.986T>C - 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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Mus musculus reticulon 4 (Rtn4), transcript variant 5, mRNA
Mus musculus reticulon 4 (Rtn4), transcript variant 5, mRNA
gi|34610236|ref|NM_194051.1|

Nucleotide
Mus musculus plexin A3, mRNA (cDNA clone MGC:118733 IMAGE:30945372), complete cd...
Mus musculus plexin A3, mRNA (cDNA clone MGC:118733 IMAGE:30945372), complete cds
gi|146141256|gb|BC093482.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000909168	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 12, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19026292, 23064986, 25741868
SCV001508839	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Oct 16, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19026292, 23064986, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909168

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 12, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV001508839

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Oct 16, 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

Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia.

Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, Araujo L, Vohra Y, Defesche JC, Wilson JM, Rader DJ.

Am J Cardiol. 2008 Dec 1;102(11):1438-43. doi: 10.1016/j.amjcard.2008.07.035. Epub 2008 Sep 11.

PubMed [citation]

PMID:: 19026292

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909168.4

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

Description

This missense variant (also known as p.Leu435Pro in the mature protein) replaces leucine with proline at codon 456 of the LDLR 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with familial hypercholesterolemia (PMID: 23064986). This variant has also been observed in compound heterozygous state in an individual affected with homozygous familial hypercholesterolemia (PMID: 19026292), indicating that this variant contributes to disease. This variant has been identified in 1/250860 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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, SCV001508839.3

#	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 proline, which is neutral and non-polar, at codon 456 of the LDLR protein (p.Leu456Pro). This variant is present in population databases (rs200143634, gnomAD 0.007%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 19026292, 23064986). This variant is also known as L435P. ClinVar contains an entry for this variant (Variation ID: 440637). 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. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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: Sep 29, 2024

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