NM_000527.5(LDLR):c.1727A>C (p.Tyr576Ser) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Mar 25, 2016
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:: RCV000237268.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1727A>C (p.Tyr576Ser)]

NM_000527.5(LDLR):c.1727A>C (p.Tyr576Ser)

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.1727A>C (p.Tyr576Ser)

HGVS:

NC_000019.10:g.11116880A>C
NG_009060.1:g.32500A>C
NM_000527.5:c.1727A>CMANE SELECT
NM_001195798.2:c.1727A>C
NM_001195799.2:c.1604A>C
NM_001195800.2:c.1223A>C
NM_001195803.2:c.1346A>C
NP_000518.1:p.Tyr576Ser
NP_001182727.1:p.Tyr576Ser
NP_001182728.1:p.Tyr535Ser
NP_001182729.1:p.Tyr408Ser
NP_001182732.1:p.Tyr449Ser
LRG_274:g.32500A>C
NC_000019.9:g.11227556A>C
c.1727A>C

Protein change:

Y408S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001152; dbSNP: rs879254999

NCBI 1000 Genomes Browser:

rs879254999

Molecular consequence:

NM_000527.5:c.1727A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1727A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1604A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1223A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1346A>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
SCV000295615	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,
SCV004022249	deCODE genetics, Amgen	no assertion criteria provided	Likely pathogenic (Jul 21, 2023)	germline	research

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295615

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,

SCV004022249

deCODE genetics, Amgen

no assertion criteria provided

Likely pathogenic
(Jul 21, 2023)

germline

research

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
Icelandic	germline	yes	11	not provided	not provided	not provided	not provided	research

Citations

PubMed

Molecular spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295615.2

#	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 deCODE genetics, Amgen, SCV004022249.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Icelandic	11	not provided	not provided	research	not provided

Description

The variant NM_000527.5:c.1727A>C (chr19:11116880) in LDLR was detected in 7 heterozygotes out of 58K WGS Icelanders (MAF= 0,006%). Following imputation in a set of 166K Icelanders (11 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 1.88, P= 1.57e-06) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 1.87, P= 1.82e-06). This variant has been reported in ClinVar previously as likely pathogenic. Based on ACMG criteria (PS4, PM1, PP3, PP5) this variant classifies as likely pathogenic.

#	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		11	not provided	not provided	not provided

Last Updated: Feb 4, 2024

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