NM_000527.5(LDLR):c.1801G>C (p.Asp601His) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Feb 27, 2023
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:: RCV002518489.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1801G>C (p.Asp601His)]

NM_000527.5(LDLR):c.1801G>C (p.Asp601His)

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.1801G>C (p.Asp601His)

HGVS:

NC_000019.10:g.11116954G>C
NG_009060.1:g.32574G>C
NM_000527.5:c.1801G>CMANE SELECT
NM_001195798.2:c.1801G>C
NM_001195799.2:c.1678G>C
NM_001195800.2:c.1297G>C
NM_001195803.2:c.1420G>C
NP_000518.1:p.Asp601His
NP_000518.1:p.Asp601His
NP_001182727.1:p.Asp601His
NP_001182728.1:p.Asp560His
NP_001182729.1:p.Asp433His
NP_001182732.1:p.Asp474His
LRG_274t1:c.1801G>C
LRG_274:g.32574G>C
LRG_274p1:p.Asp601His
NC_000019.9:g.11227630G>C
NM_000527.4:c.1801G>C
P01130:p.Asp601His
c.1801G>C

Protein change:

D433H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001004; UniProtKB: P01130#VAR_072857

Molecular consequence:

NM_000527.5:c.1801G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1801G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1678G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1297G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1420G>C - 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
SCV000295665	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 25461735, 33231818, 11933210 Citation Link,
SCV003520106	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 27, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11933210, 25461735, 33231818, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295665

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Uncertain significance
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV003520106

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 27, 2023)

germline

clinical testing

PubMed (4)
[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	clinical testing

Citations

PubMed

Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

Salazar LA, Hirata MH, Cavalli SA, Nakandakare ER, Forti N, Diament J, Giannini SD, Bertolami MC, Hirata RD.

Hum Mutat. 2002 Apr;19(4):462-3.

PubMed [citation]

PMID:: 11933210

Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.

Jannes CE, Santos RD, de Souza Silva PR, Turolla L, Gagliardi AC, Marsiglia JD, Chacra AP, Miname MH, Rocha VZ, Filho WS, Krieger JE, Pereira AC.

Atherosclerosis. 2015 Jan;238(1):101-7. doi: 10.1016/j.atherosclerosis.2014.11.009. Epub 2014 Nov 14.

PubMed [citation]

PMID:: 25461735

See all PubMed Citations (4)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295665.3

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

Description

NM_000527.5(LDLR):c.1801G>C (p.Asp601His) has been reported in South America (PMID: 11933210; 25461735), with a definitive FH case in PMID: 33231818, allowing ACMG criteria PP4 to be scored. PM2 can also be scored, however, PP3 can not be scored as the REVEL score of 0.605 is below the threshold of >0.75 for a pathogenic prediction. The overall classification for this variant is Uncertain significance.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003520106.2

#	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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 601 of the LDLR protein (p.Asp601His). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11933210, 25461735, 33231818). ClinVar contains an entry for this variant (Variation ID: 252038). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on LDLR protein function. This variant disrupts the p.Asp601 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (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

Last Updated: Sep 29, 2024

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