NM_000527.5(LDLR):c.1898G>A (p.Arg633His) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 29, 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:: RCV001188072.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1898G>A (p.Arg633His)]

NM_000527.5(LDLR):c.1898G>A (p.Arg633His)

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.1898G>A (p.Arg633His)

HGVS:

NC_000019.10:g.11120144G>A
NG_009060.1:g.35764G>A
NM_000527.5:c.1898G>AMANE SELECT
NM_001195798.2:c.1898G>A
NM_001195799.2:c.1775G>A
NM_001195800.2:c.1394G>A
NM_001195803.2:c.1517G>A
NP_000518.1:p.Arg633His
NP_000518.1:p.Arg633His
NP_001182727.1:p.Arg633His
NP_001182728.1:p.Arg592His
NP_001182729.1:p.Arg465His
NP_001182732.1:p.Arg506His
LRG_274t1:c.1898G>A
LRG_274:g.35764G>A
NC_000019.9:g.11230820G>A
NM_000527.4(LDLR):c.1898G>A
NM_000527.4:c.1898G>A
c.1898G>A
p.(Arg633His)
p.Arg633His

Protein change:

R465H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001073; dbSNP: rs754536745

NCBI 1000 Genomes Browser:

rs754536745

Molecular consequence:

NM_000527.5:c.1898G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1898G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1775G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1394G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1517G>A - 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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ADAM8 protein [Homo sapiens]
ADAM8 protein [Homo sapiens]
gi|109731932|gb|AAI15405.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001355021	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 13, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 15823288, 16250003, 20506408, 26228681, 27784735, 30270359, 33418990, 34297352, 35928446, 37119068, 25741868
SCV001461323	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001575965	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 15823288, 16250003, 19843101, 9259195, 15241806, 23375686, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001355021

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 13, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001461323

Natera, Inc.

no assertion criteria provided

Likely pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV001575965

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (7)
[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

Functionality of sequence variants in the genes coding for the low-density lipoprotein receptor and apolipoprotein B in individuals with inherited hypercholesterolemia.

Huijgen R, Kindt I, Fouchier SW, Defesche JC, Hutten BA, Kastelein JJ, Vissers MN.

Hum Mutat. 2010 Jun;31(6):752-60. doi: 10.1002/humu.21258.

PubMed [citation]

PMID:: 20506408

Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide.

Roeters van Lennep J, Averna M, Alonso R.

J Clin Lipidol. 2015 Jul-Aug;9(4):607-17. doi: 10.1016/j.jacl.2015.05.001. Epub 2015 May 14.

PubMed [citation]

PMID:: 26228681

See all PubMed Citations (16)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001355021.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces arginine with histidine at codon 633 of the LDLR protein. This variant is also known as p.Arg612His in the mature protein. This variant alters a conserved arginine residue in the LDLR type B repeat 6 of the EGF precursor homology domain of the LDLR protein (a.a. 616 - 658), where pathogenic missense variants are found enriched (ClinVar-LDLR). 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 individuals affected with familial hypercholesterolemia (PMID: 15823288, 16250003, 20506408, 30270359, 33418990, 34297352, 35928446, 37119068), including in the compound heterozygous state with a second pathogenic LDLR variant in individuals affected with severe homozygous familial hypercholesterolemia (PMID: 26228681, 27784735). This variant has been identified in 6/282886 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants affecting the same codon, p.Arg633Cys and p.Arg633Leu, are considered to be disease-causing (ClinVar Variation ID: 226379 and 252107), suggesting that arginine at this position is important for LDLR protein function. 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 Natera, Inc., SCV001461323.1

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

#	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, SCV001575965.4

#	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 arginine, which is basic and polar, with histidine, which is basic and polar, at codon 633 of the LDLR protein (p.Arg633His). This variant is present in population databases (rs754536745, gnomAD 0.01%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 15823288, 16250003, 19843101; Invitae). This variant is also known as R612H. ClinVar contains an entry for this variant (Variation ID: 226380). 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.Arg633 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9259195, 15241806, 23375686). 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

Last Updated: Oct 20, 2024

ClinVar

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