NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp) AND Hypercholesterolemia, familial, 1

Germline classification:: Pathogenic (17 submissions)
Last evaluated:: Apr 22, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000211575.30

Allele description [Variation Report for NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)]

NM_000527.5(LDLR):c.1216C>T (p.Arg406Trp)

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.1216C>T (p.Arg406Trp)

Other names:

FH Rumania; NM_000527.5(LDLR):c.1216C>T

HGVS:

NC_000019.10:g.11113307C>T
NG_009060.1:g.28927C>T
NM_000527.5:c.1216C>TMANE SELECT
NM_001195798.2:c.1216C>T
NM_001195799.2:c.1093C>T
NM_001195800.2:c.712C>T
NM_001195803.2:c.835C>T
NP_000518.1:p.Arg406Trp
NP_000518.1:p.Arg406Trp
NP_001182727.1:p.Arg406Trp
NP_001182728.1:p.Arg365Trp
NP_001182729.1:p.Arg238Trp
NP_001182732.1:p.Arg279Trp
LRG_274t1:c.1216C>T
LRG_274:g.28927C>T
NC_000019.9:g.11223983C>T
NM_000527.4(LDLR):c.1216C>T
NM_000527.4:c.1216C>T
P01130:p.Arg406Trp
c.1216C>T

Protein change:

R238W

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000177; UniProtKB: P01130#VAR_072847

Molecular consequence:

NM_000527.5:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1216C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1093C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.712C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.835C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

Clear Turn Off Turn On

CD72 [Macaca nemestrina]
CD72 [Macaca nemestrina]
Gene ID:105485725

Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268604	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741862, 25741868
SCV000295306	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 8882879, 20538126, 17765246, 19318025, 26343872 Citation Link,
SCV000322937	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25741862
SCV000503317	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000583806	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000588566	Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25741862
SCV000606362	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV000607575	Fundacion Hipercolesterolemia Familiar - SAFEHEART	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25741862
SCV000748143	Iberoamerican FH Network	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 25741862
SCV000987565	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001422933	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 22, 2020)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 17765246, 26343872, 8882879, 25741862, 20538126, 25741868 Citation Link,
SCV001432550	Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 7, 2018)	germline	research	PubMed (2) [See all records that cite these PMIDs] 25741868, 31345425
SCV002506381	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Pathogenic (Apr 22, 2022)	germline	curation	Citation Link,
SCV002538606	Laan Lab, Human Genetics Research Group, University of Tartu	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 1, 2021)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 35535697, 25741868
SCV002809698	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003819487	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004831709	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 28, 2023)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 8882879, 17694954, 17765246, 20538126, 25461735, 25741862, 26020417, 26343872, 28502495, 30876530, 32331935, 33533259, 33994402, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	19	1	not provided	2606	not provided	clinical testing, research, literature only
not provided	germline	unknown	4	not provided	not provided	108544	not provided	clinical testing, research, curation
not provided	unknown	unknown	1	not provided	not provided	not provided	not provided	clinical testing, research

Citations

PubMed

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

Risk of Premature Atherosclerotic Disease in Patients With Monogenic Versus Polygenic Familial Hypercholesterolemia.

Trinder M, Li X, DeCastro ML, Cermakova L, Sadananda S, Jackson LM, Azizi H, Mancini GBJ, Francis GA, Frohlich J, Brunham LR.

J Am Coll Cardiol. 2019 Jul 30;74(4):512-522. doi: 10.1016/j.jacc.2019.05.043.

PubMed [citation]

PMID:: 31345425

See all PubMed Citations (17)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268604.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The LDLR p.Arg406Trp variant has been described in multiple cohorts of familial hypercholesterolemia patients and their families, and in vitro studies have showed a 40% reduction in LDL-receptor activity compared to wild-type LDL-receptor (PMID: 25741862).

#	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 LDLR-LOVD, British Heart Foundation, SCV000295306.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (5)
2	not provided	1	not provided	not provided	literature only	PubMed (5)
3	not provided	1	not provided	not provided	literature only	PubMed (5)
4	not provided	1	not provided	not provided	literature only	PubMed (5)
5	not provided	1	not provided	not provided	literature only	PubMed (5)

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

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322937.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF (ExAC):0.001665

"Heterologous cells (CHO), FACS and WB assays"

PubMed [ID: 25741862]

Description

0/208 non-FH alleles; 0/100 healthy control individuals

#	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
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503317.1

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

Description

subjects mutated among 2600 FH index cases screened = 11 , family members = 7 with co-segregation / previously described in association with FH/Software predictions: Benign

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		11	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583806.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

Dutch Lipid Clinic Scoring : Definite FH

#	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		2	not provided	1	not provided

From Laboratory of Genetics and Molecular Cardiology, University of São Paulo - HipercolBrasil, SCV000588566.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF(ExAC):0.001665

"Assay description:Heterologous cells (CHO), FACS and WB assays"

PubMed [ID: 25741862]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606362.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Fundacion Hipercolesterolemia Familiar - SAFEHEART, SCV000607575.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF(ExAC):0.001665

"Heterologous cells (CHO), FACS and WB assays"

PubMed [ID: 25741862]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Iberoamerican FH Network, SCV000748143.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (2)
2	not provided	not provided	not provided	not provided	research	PubMed (2)

Description

%MAF(ExAC):0.001665

"Assay Description:Heterologous cells (CHO), FACS and WB assays"

PubMed [ID: 25741862]

#	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
2	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV000987565.1

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

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001422933.2

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

Description

The p.Arg406Trp variant in LDLR has been reported in at least 51 individuals (including 48 Portuguese, 1 Taiwanese, 1 Korean, and 1 Ashkenazi Jewish individuals) with Familial Hypercholesterolemia, segregated with disease in 48 affected relatives from 18 families (PMID: 17765246, 20538126, 26343872, 8882879, 25741862), and has been identified in 0.009658% (1/10354) of Ashkenazi Jewish chromosomes and 0.008021% (2/24936) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908043). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic and pathogenic in ClinVar (Variation ID: 226351). In vitro functional studies provide some evidence that the p.Arg406Trp variant may impact cell surface expression and receptor activity (PMID: 25741862). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on cosegregation with disease and multiple reports in individuals with Familial Hypercholesterolemia. ACMG/AMP Criteria applied: PP1_Strong, PS4, PS3_supporting, PP3 (Richards 2015).

#	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 Brunham Lab, Centre for Heart and Lung Innovation, University of British Columbia, SCV001432550.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

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

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506381.2

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

Description

The NM_000527.5(LDLR):c1216C>T (p.Arg406Trp) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PS3, PS4, PP1_Strong, and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PM2 - PopMax MAF = 0.000097 (0.0097%) in Ashkenazi Jewish exomes+genomes (gnomAD v2.1.1). PP3 - REVEL = 0.88, which is above the threshold of 0.75. PS3 – Level 1 functional studies: PMID: 2574186; Heterologous cells (CHO), FACS assays - variant results in 60-65% LDLR expression/biosynthesis, LDL binding and LDL internalization compared to wild-type; results meet <70% threshold. PS4 – Variant meets PM2 and is identified in at least 19 unrelated index cases who fulfill clinical criteria for FH (1 case with DLCN criteria from PathWest Laboratory Medicine WA – FH VCEP member lab; 18 cases with SB criteria from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – FH VCEP member lab). PP1_Strong – Variant segregates with phenotype in 31 informative meioses from 15 families in data provided by FH VCEP member labs (Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge – 11 families: 23 affected with the variant and 1 unaffected without the variant; Laboratory of Genetics and Molecular Cardiology – 4 families: 4 affected with the variant and 3 unaffected without the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded. Note: two other missense variants at this same codon have been reported: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) – Likely pathogenic by these guidelines. -PM5 not applicable as such variants must be 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 Laan Lab, Human Genetics Research Group, University of Tartu, SCV002538606.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

#	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		1	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002809698.1

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

#	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

From Revvity Omics, Revvity, SCV003819487.2

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

#	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 All of Us Research Program, National Institutes of Health, SCV004831709.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (14)

Description

This missense variant replaces arginine with tryptophan at codon 406 of the LDLR protein. It is also known as p.Arg385Trp in the mature 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). Functional studies have shown that this variant causes partial reduction of LDLR activity by about 40% compared to wild-type (PMID: 25741862). This LDLR variant has been reported in individuals affected with autosomal dominant familial hypercholesterolemia (PMID: 8882879, 17694954, 17765246, 20538126, 25461735, 26020417, 26343872, 28502495, 30876530, 32331935, 33533259, 33994402). This variant has also been observed in both homozygous and compound heterozygous state with a known pathogenic LDLR variant in individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 20538126, 26020417). This variant has been identified in 5/282390 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg406Gln and p.Arg406Pro, are known to cause disease (ClinVar Variation ID: 228798, 226352), indicating that arginine at this position may be 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	108544	not provided	not provided		4	not provided	not provided	not provided

Last Updated: Oct 20, 2024

Relating variation to medicine