NM_000527.5(LDLR):c.632A>T (p.His211Leu) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Dec 28, 2023
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:: RCV001345581.8

Allele description [Variation Report for NM_000527.5(LDLR):c.632A>T (p.His211Leu)]

NM_000527.5(LDLR):c.632A>T (p.His211Leu)

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.632A>T (p.His211Leu)

HGVS:

NC_000019.10:g.11105538A>T
NG_009060.1:g.21158A>T
NM_000527.5:c.632A>TMANE SELECT
NM_001195798.2:c.632A>T
NM_001195799.2:c.509A>T
NM_001195800.2:c.314-1854A>T
NM_001195803.2:c.314-1027A>T
NP_000518.1:p.His211Leu
NP_000518.1:p.His211Leu
NP_001182727.1:p.His211Leu
NP_001182728.1:p.His170Leu
LRG_274t1:c.632A>T
LRG_274:g.21158A>T
LRG_274p1:p.His211Leu
NC_000019.9:g.11216214A>T
NM_000527.4:c.632A>T
P01130:p.His211Leu
c.632A>T

Protein change:

H170L

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001255; UniProtKB: P01130#VAR_072834; dbSNP: rs879254603

NCBI 1000 Genomes Browser:

rs879254603

Molecular consequence:

NM_001195800.2:c.314-1854A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1027A>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.632A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.632A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.509A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV001539711	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17347910, 10570905, 21511053, 28492532
SCV002086373	Natera, Inc.	no assertion criteria provided	Uncertain significance (Oct 22, 2020)	germline	clinical testing
SCV005045760	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001539711

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 28, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002086373

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Oct 22, 2020)

germline

clinical testing

SCV005045760

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Oct 1, 2021)

unknown

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations.

Widhalm K, Dirisamer A, Lindemayr A, Kostner G.

J Inherit Metab Dis. 2007 Apr;30(2):239-47. Epub 2007 Mar 8.

PubMed [citation]

PMID:: 17347910

A novel LDLR mutation, H190Y, in a Utah kindred with familial hypercholesterolemia.

Hopkins PN, Wu LL, Stephenson SH, Xin Y, Katsumata H, Nobe Y, Nakajima T, Hirayama T, Emi M, Williams RR.

J Hum Genet. 1999;44(6):364-7.

PubMed [citation]

PMID:: 10570905

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001539711.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 211 of the LDLR protein (p.His211Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 17347910; Invitae). This variant is also known as p.His190Leu. ClinVar contains an entry for this variant (Variation ID: 251337). 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%. This variant disrupts the p.His211 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10570905, 21511053; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Natera, Inc., SCV002086373.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV005045760.1

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

Description

Automatically set to LPath based on study of VUS-LP variants

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

Last Updated: Sep 29, 2024

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