NM_000527.5(LDLR):c.1898G>A (p.Arg633His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 12, 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:: RCV001090454.20

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001246011	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Oct 1, 2019)	germline	clinical testing	Citation Link,
SCV003918455	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Apr 12, 2023)	germline	clinical testing	Citation Link,
SCV004219965	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Nov 22, 2022)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 30270359, 15823288, 27578128, 34297352, 33418990, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001246011

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Oct 1, 2019)

germline

clinical testing

Citation Link,

SCV003918455

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Apr 12, 2023)

germline

clinical testing

Citation Link,

SCV004219965

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Nov 22, 2022)

unknown

clinical testing

PubMed (6)
[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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Recall by genotype and cascade screening for familial hypercholesterolemia in a population-based biobank from Estonia.

Alver M, Palover M, Saar A, Läll K, Zekavat SM, Tõnisson N, Leitsalu L, Reigo A, Nikopensius T, Ainla T, Kals M, Mägi R, Gabriel SB, Eha J, Lander ES, Irs A, Philippakis A, Marandi T, Natarajan P, Metspalu A, Kathiresan S, Esko T.

Genet Med. 2019 May;21(5):1173-1180. doi: 10.1038/s41436-018-0311-2. Epub 2018 Oct 1.

PubMed [citation]

PMID:: 30270359
PMCID:: PMC6443485

The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.

Damgaard D, Larsen ML, Nissen PH, Jensen JM, Jensen HK, Soerensen VR, Jensen LG, Faergeman O.

Atherosclerosis. 2005 May;180(1):155-60. Epub 2005 Jan 12.

PubMed [citation]

PMID:: 15823288

See all PubMed Citations (6)

Details of each submission

From CeGaT Center for Human Genetics Tuebingen, SCV001246011.22

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

From GeneDx, SCV003918455.1

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.R612H; This variant is associated with the following publications: (PMID: 22390909, 27578128, 31447099, 16250003, 28235710, 17539906, 9259195, 32719484, 34297352, 33418990, 23375686, 26228681, 20506408, 34037665, 34456049, 19318025, 19843101, 30270359, 15823288, 27784735)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219965.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The frequency of this variant in the general population, 0.000023 (3/129190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in patients with familial hypercholesterolemia (PMIDs: 15823288 (2005), 16250003 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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