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

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 12, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004017507.1

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:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004847737	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 12, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16250003, 22390909, 27578128, 15823288, 30270359, 34037665, 33418990, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004847737

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 12, 2022)

germline

clinical testing

PubMed (8)
[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

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

Cardiovascular risk in relation to functionality of sequence variants in the gene coding for the low-density lipoprotein receptor: a study among 29,365 individuals tested for 64 specific low-density lipoprotein-receptor sequence variants.

Huijgen R, Kindt I, Defesche JC, Kastelein JJ.

Eur Heart J. 2012 Sep;33(18):2325-30. doi: 10.1093/eurheartj/ehs038. Epub 2012 Mar 4.

PubMed [citation]

PMID:: 22390909

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847737.1

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

Description

The p.Arg633His variant in LDLR (also described as p.Arg612His in the literature) has been reported in at least 9 individuals with familial hypercholesterolemia (FH), including 2 compound heterozygotes (Fouchier 2005 PMID: 16250003, Damgaard 2005 PMID: 15823288, Huijgen 2012 PMID: 22390909, Alonso 2016 PMID: 27578128, Alver 2019 PMID: 30270359, Meshkov 2020 PMID: 33418990, Sturm 2021 PMID: 34037665). It has also been reported by other clinical laboratories in ClinVar (Variation ID: 226380) and has been identified in 0.007% (2/30616) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of FH in the general population. Computational prediction tools and conservation analyses are consistent with pathogenicity. Another variant involving this codon (p.Arg633Cys) has been identified in individuals with FH and is classified as likely pathogenic by this laboratory. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant FH. ACMG/AMP Criteria applied: PM2_Supporting, PM5, PP3, PS4_Moderate.

#	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

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