NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (5 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:: RCV000211629.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro)]

NM_000527.5(LDLR):c.1217G>C (p.Arg406Pro)

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.1217G>C (p.Arg406Pro)

Other names:

NM_000527.5(LDLR):c.1217G>C

HGVS:

NC_000019.10:g.11113308G>C
NG_009060.1:g.28928G>C
NM_000527.5:c.1217G>CMANE SELECT
NM_001195798.2:c.1217G>C
NM_001195799.2:c.1094G>C
NM_001195800.2:c.713G>C
NM_001195803.2:c.836G>C
NP_000518.1:p.Arg406Pro
NP_000518.1:p.Arg406Pro
NP_001182727.1:p.Arg406Pro
NP_001182728.1:p.Arg365Pro
NP_001182729.1:p.Arg238Pro
NP_001182732.1:p.Arg279Pro
LRG_274t1:c.1217G>C
LRG_274:g.28928G>C
LRG_274p1:p.Arg406Pro
NC_000019.9:g.11223984G>C
NM_000527.4:c.1217G>C
c.1217G>C

Protein change:

R238P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000651; dbSNP: rs552422789

NCBI 1000 Genomes Browser:

rs552422789

Molecular consequence:

NM_000527.5:c.1217G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1217G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1094G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.713G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.836G>C - 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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000268605	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Mar 22, 2013)	germline	clinical testing
SCV000295308	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 22698793, 16250003, 17094996 Citation Link,
SCV000540802	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV000606364	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002506382	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Apr 22, 2022)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	3	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
Caucasian	inherited	yes	2	1	not provided	3964	yes	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

Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.

Tosi I, Toledo-Leiva P, Neuwirth C, Naoumova RP, Soutar AK.

Atherosclerosis. 2007 Sep;194(1):102-11. Epub 2006 Nov 13.

PubMed [citation]

PMID:: 17094996

See all PubMed Citations (4)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268605.1

#	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 LDLR-LOVD, British Heart Foundation, SCV000295308.2

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

#	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

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540802.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		2	not provided	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606364.1

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506382.1

#	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):c1217G>C (p.Arg406Pro) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP3, PM5, PS4_Supporting, PP1, 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 - This variant is absent from gnomAD (gnomAD v2.1.1). PP3 - REVEL = 0.89, which is above the threshold of 0.75. PM5 - 2 other missense variants in the same codon: 1) NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) – Likely pathogenic by these guidelines. 2) NM_000527.5(LDLR):c.1217G>C (p.Arg406Trp) – Pathogenic by these guidelines. There is 1 variant in the same codon classified as Pathogenic by these guidelines. – therefore PM5 is met. PS4_Supporting - Variant meets PM2 and is identified in 2 unrelated index cases who fulfill clinical criteria for FH (1 case with SB criteria from Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation– FH VCEP member lab; 1 case with DLCN criteria from PMID: 16250003) PP1 - Variant segregates with phenotype in 2 informative meioses from 2 families in data provided by FH VCEP member labs (Laboratory of Genetics and Molecular Cardiology – 1 family: 1 affected family member with the variant; Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation – 1 family: 1 affected family member with the variant). PP4 - Variant meets PM2. Identified in >1 case who met clinical criteria for FH after alternative causes for high cholesterol were excluded.

#	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: Jun 23, 2024

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