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

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 28, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000775082.15

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]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627024	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20809525, 28964736, 28492532
SCV000909186	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 26, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001482447	Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	research	PubMed (2) [See all records that cite these PMIDs] 29261184, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627024

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 28, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000909186

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 26, 2020)

germline

clinical testing

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

SCV001482447

Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance

germline

research

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	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Efficacy of alirocumab in 1191 patients with a wide spectrum of mutations in genes causative for familial hypercholesterolemia.

Defesche JC, Stefanutti C, Langslet G, Hopkins PN, Seiz W, Baccara-Dinet MT, Hamon SC, Banerjee P, Kastelein JJP.

J Clin Lipidol. 2017 Nov - Dec;11(6):1338-1346.e7. doi: 10.1016/j.jacl.2017.08.016. Epub 2017 Sep 4. Erratum in: J Clin Lipidol. 2020 Sep - Oct;14(5):742. doi: 10.1016/j.jacl.2020.09.010.

PubMed [citation]

PMID:: 28964736

See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000627024.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 652 of the LDLR protein (p.Met652Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 20809525, 28964736; Invitae). ClinVar contains an entry for this variant (Variation ID: 226382). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as 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 Color Diagnostics, LLC DBA Color Health, SCV000909186.3

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

Description

This missense variant (also known as p.Met631Thr in the mature protein) replaces methionine with threonine at codon 652 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with familial hypercholesterolemia (PMID: 20236128, 20809525, 22883975, 28964736). It has been shown that this variant segregates with disease in one family (Al-Olabi et al 2019). This variant has been identified in 1/251458 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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 Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine, SCV001482447.1

#	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

Last Updated: Aug 11, 2024

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