NM_000527.5(LDLR):c.137G>C (p.Cys46Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Mar 25, 2016
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:: RCV000003940.8

Allele description [Variation Report for NM_000527.5(LDLR):c.137G>C (p.Cys46Ser)]

NM_000527.5(LDLR):c.137G>C (p.Cys46Ser)

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.137G>C (p.Cys46Ser)

Other names:

LDLR, CYS25SER

HGVS:

NC_000019.10:g.11100292G>C
NG_009060.1:g.15912G>C
NM_000527.5:c.137G>CMANE SELECT
NM_001195798.2:c.137G>C
NM_001195799.2:c.137G>C
NM_001195800.2:c.137G>C
NM_001195803.2:c.137G>C
NP_000518.1:p.Cys46Ser
NP_000518.1:p.Cys46Ser
NP_001182727.1:p.Cys46Ser
NP_001182728.1:p.Cys46Ser
NP_001182729.1:p.Cys46Ser
NP_001182732.1:p.Cys46Ser
LRG_274t1:c.137G>C
LRG_274:g.15912G>C
LRG_274p1:p.Cys46Ser
NC_000019.9:g.11210968G>C
NM_000527.4:c.137G>C
P01130:p.Cys46Ser
c.137G>C

Protein change:

C46S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000449; UniProtKB: P01130#VAR_013949; OMIM: 606945.0061; dbSNP: rs121908041

NCBI 1000 Genomes Browser:

rs121908041

Molecular consequence:

NM_000527.5:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.137G>C - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000024105	OMIM	no assertion criteria provided	Pathogenic (Apr 1, 2001)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000294480	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000599314	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 11298688

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024105

OMIM

no assertion criteria provided

Pathogenic
(Apr 1, 2001)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000294480

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000599314

Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 1, 2016)

germline, not applicable

curation, literature only

PubMed (2)
[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	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

A novel mutation in exon 2 of the low-density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia.

Takahashi M, Ikeda U, Takahashi S, Hattori H, Iwasaki T, Ishihara M, Egashira T, Honma S, Asano Y, Shimada K.

Clin Genet. 2001 Apr;59(4):290-2. No abstract available.

PubMed [citation]

PMID:: 11298688

Details of each submission

From OMIM, SCV000024105.3

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

Description

In a Japanese patient with familial hypercholesterolemia (FHCL1; 143890), Takahashi et al. (2001) identified a G-to-C transversion at nucleotide 137 of the LDLR gene, resulting in a cys25-to-ser (C25S) amino acid substitution in the ligand-binding site (mutation class 2B: slow transport and processing). The patient first noticed xanthomas on both elbows at the age of 5 years. These continued to increase in number and size. At age 40 years, xanthomas were present on elbows, palms, knees, and feet. Clinical manifestations of myocardial ischemia developed at age 41. Selective LDL filtration was initiated after plasma apheresis through a macromolecular exclusion filter. With bimonthly treatments, her LDL cholesterol decreased by approximately 50% and the xanthomas regressed markedly, almost disappearing with 5 years of treatment.

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

From LDLR-LOVD, British Heart Foundation, SCV000294480.2

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

#	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 Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599314.1

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

Description

"Assay Description:Hmz patients' lymphocytes, FACS and ligand binding assays"

PubMed [ID: 11298688]

#	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	not applicable	not applicable	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Aug 5, 2023

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