NM_000527.5(LDLR):c.1955T>C (p.Met652Thr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Aug 29, 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:: RCV000211590.13

Allele description [Variation Report for NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)]

NM_000527.5(LDLR):c.1955T>C (p.Met652Thr)

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.1955T>C (p.Met652Thr)

Other names:

NM_000527.5(LDLR):c.1955T>C

HGVS:

NC_000019.10:g.11120201T>C
NG_009060.1:g.35821T>C
NM_000527.5:c.1955T>CMANE SELECT
NM_001195798.2:c.1955T>C
NM_001195799.2:c.1832T>C
NM_001195800.2:c.1451T>C
NM_001195803.2:c.1574T>C
NP_000518.1:p.Met652Thr
NP_000518.1:p.Met652Thr
NP_001182727.1:p.Met652Thr
NP_001182728.1:p.Met611Thr
NP_001182729.1:p.Met484Thr
NP_001182732.1:p.Met525Thr
LRG_274t1:c.1955T>C
LRG_274:g.35821T>C
LRG_274p1:p.Met652Thr
NC_000019.9:g.11230877T>C
NM_000527.4:c.1955T>C
c.1955T>C

Protein change:

M484T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000266; dbSNP: rs875989936

NCBI 1000 Genomes Browser:

rs875989936

Molecular consequence:

NM_000527.5:c.1955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1955T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1832T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1451T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1574T>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
SCV000268651	Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	no assertion criteria provided	Pathogenic (Jun 25, 2008)	germline	clinical testing
SCV000295774	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 20809525, 20236128 Citation Link,
SCV000503437	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]
SCV000583911	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002817176	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Aug 29, 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	7	2	not provided	2602	not provided	clinical testing, literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

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

Mutation detection rate and spectrum in familial hypercholesterolaemia patients in the UK pilot cascade project.

Taylor A, Wang D, Patel K, Whittall R, Wood G, Farrer M, Neely RD, Fairgrieve S, Nair D, Barbir M, Jones JL, Egan S, Everdale R, Lolin Y, Hughes E, Cooper JA, Hadfield SG, Norbury G, Humphries SE.

Clin Genet. 2010 Jun;77(6):572-80. doi: 10.1111/j.1399-0004.2009.01356.x. Epub 2010 Mar 13.

PubMed [citation]

PMID:: 20236128

See all PubMed Citations (3)

Details of each submission

From Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital, SCV000268651.1

#	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, SCV000295774.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (2)
2	not provided	1	not provided	not provided	literature only	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
2	germline	yes	1	not provided	not provided		1	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, SCV000503437.1

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

Description

subjects mutated among 2600 FH index cases screened = 2 / Other mutation at same codon/Software predictions: Conflicting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		2	not provided	not provided	not provided

From U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583911.1

#	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	2	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817176.1

#	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):c.1955T>C (p.Met652Thr) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PM2, PP4, PP1_Moderate and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follow: PM2_ Met : Allele frequency is 0.00005 (18394 alleles) in the East Asian subpopulation in GnomAD (gnomAD v2.1.1). PP4_Met : 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA - as defined by DLCN>6 and 1 from PMID: 20236128 as defined by Simon Broome score = definite). PS4_Supporting: 2 patients with definite FH (1 from the Cardiovascular Genetics Laboratory - PathWest Laboratory Medicine WA -with DLCN>6 and 1 from PMID: 20236128 with Simon Broome score = definite) and 1 case with untreated LDL-C=348 (Ambry Genetics). PMID:20829525 1 carrier was identified but the FH phenotype was evaluated only considering total and LDL-cholesterol levels above the 95 th percentile when compared with a sex- and age-matched French population. I will not consider this patient. PMID:22883975 1 carrier with clinical FH defined by DLCN score was reported. However, it is impossible to understand if the patient carrying the variant has a DLCN>6. I will not consider this patient. PMID: 28964736 1 carrier with clinical FH was reported in the cohort of ALTERNATIVE study which did not have a recorded diagnosis of FH, as they had very high baseline LDL-C levels (>5.0 mmol/L, ∼193 mg/dL).No data on FH its FC classification is reported. I will not consider this patient. PP1_Strong : Variant segregates with phenotype in 5 relatives in 1 family. (8 informative meiosis)

#	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: Aug 11, 2024

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