NM_000527.5(LDLR):c.1243G>C (p.Asp415His) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 12, 2021
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:: RCV001174782.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1243G>C (p.Asp415His)]

NM_000527.5(LDLR):c.1243G>C (p.Asp415His)

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.1243G>C (p.Asp415His)

HGVS:

NC_000019.10:g.11113334G>C
NG_009060.1:g.28954G>C
NM_000527.5:c.1243G>CMANE SELECT
NM_001195798.2:c.1243G>C
NM_001195799.2:c.1120G>C
NM_001195800.2:c.739G>C
NM_001195803.2:c.862G>C
NP_000518.1:p.Asp415His
NP_000518.1:p.Asp415His
NP_001182727.1:p.Asp415His
NP_001182728.1:p.Asp374His
NP_001182729.1:p.Asp247His
NP_001182732.1:p.Asp288His
LRG_274t1:c.1243G>C
LRG_274:g.28954G>C
LRG_274p1:p.Asp415His
NC_000019.9:g.11224010G>C
NM_000527.4:c.1243G>C
c.1243G>C

Protein change:

D247H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000538; dbSNP: rs879254844

NCBI 1000 Genomes Browser:

rs879254844

Molecular consequence:

NM_000527.5:c.1243G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1243G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1120G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.739G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.862G>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
SCV001338113	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 27, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11810272, 9399845, 23833242, 22390909, 26894473, 11851376 Citation Link,
SCV003443160	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11851376, 22390909, 26894473, 23375686, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001338113

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jan 27, 2020)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV003443160

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 12, 2021)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Defesche JC, Umans-Eckenhausen MW, Kastelein JP.

Hum Genet. 2001 Dec;109(6):602-15. Epub 2001 Nov 9.

PubMed [citation]

PMID:: 11810272

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Varret M, Rabés JP, Thiart R, Kotze MJ, Baron H, Cenarro A, Descamps O, Ebhardt M, Hondelijn JC, Kostner GM, Miyake Y, Pocovi M, Schmidt H, Schuster H, Stuhrmann M, Yamamura T, Junien C, Béroud C, Boileau C.

Nucleic Acids Res. 1998 Jan 1;26(1):248-52.

PubMed [citation]

PMID:: 9399845
PMCID:: PMC147253

See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338113.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: LDLR c.1243G>C (p.Asp415His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251172 control chromosomes (gnomAD). c.1243G>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (examples- Fouchier_2001, VanGaal_2001, Huijgen_2012, Kusters_2013, Sanna_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two other ClinVar submitters (evaluation after 2014) have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003443160.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant is also known as D394H. This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 11851376, 22390909, 26894473). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 415 of the LDLR protein (p.Asp415His). ClinVar contains an entry for this variant (Variation ID: 251748). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp415 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 23375686), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.

#	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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