NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 27, 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:: RCV001526181.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)]

NM_000527.5(LDLR):c.1284C>G (p.Asn428Lys)

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.1284C>G (p.Asn428Lys)

Other names:

NM_000527.5(LDLR):c.1284C>G; p.Asn428Lys

HGVS:

NC_000019.10:g.11113375C>G
NG_009060.1:g.28995C>G
NM_000527.5:c.1284C>GMANE SELECT
NM_001195798.2:c.1284C>G
NM_001195799.2:c.1161C>G
NM_001195800.2:c.780C>G
NM_001195803.2:c.903C>G
NP_000518.1:p.Asn428Lys
NP_000518.1:p.Asn428Lys
NP_001182727.1:p.Asn428Lys
NP_001182728.1:p.Asn387Lys
NP_001182729.1:p.Asn260Lys
NP_001182732.1:p.Asn301Lys
LRG_274t1:c.1284C>G
LRG_274:g.28995C>G
LRG_274p1:p.Asn428Lys
NC_000019.9:g.11224051C>G
NM_000527.4:c.1284C>G
c.1284C>G

Protein change:

N260K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000540; dbSNP: rs368708058

NCBI 1000 Genomes Browser:

rs368708058

Molecular consequence:

NM_000527.5:c.1284C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1284C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1161C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.780C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.903C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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LOC119832192 [Zerene cesonia]
LOC119832192 [Zerene cesonia]
Gene ID:119832192

Gene
Calamus modestus (0)
Nucleotide
Nomascus leucogenys isolate Asia; international studbook 0098 contig_11783, whol...
Nomascus leucogenys isolate Asia; international studbook 0098 contig_11783, whole genome shotgun sequence
gi|305520997|gb|ADFV01111775.1||gnl ADFV01|contig_11783

Nucleotide
Vibrio parahaemolyticus S119 Contig359, whole genome shotgun sequence
Vibrio parahaemolyticus S119 Contig359, whole genome shotgun sequence
gi|647064047|ref|NZ_AWJG01000359.1| WGS:NZ_AWJG01|Contig359

Nucleotide
Vibrio parahaemolyticus S119 Contig350, whole genome shotgun sequence
Vibrio parahaemolyticus S119 Contig350, whole genome shotgun sequence
gi|647063898|ref|NZ_AWJG01000350.1| WGS:NZ_AWJG01|Contig350

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295340	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Uncertain significance (Mar 25, 2016)	germline	literature only	PubMed (5) [See all records that cite these PMIDs] 11845603, 11005141, 11668640, 11810272, 11857755 Citation Link,
SCV001736482	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 20, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11005141, 11668640, 11845603, 11857755, 14508510, 15556094, 21382890, 35047021, 36499307, 36980993, 25741868
SCV002284046	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 18, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11005141, 11238294, 11668640, 11857755, 28492532
SCV005205210	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 27, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11005141, 11238294, 11857755, 27919364, 35047021, 36752612, 36499307 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	4	not provided	literature only

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

Clinical versus molecular diagnosis of heterozygous familial hypercholesterolaemia in the diverse South African population.

Vergotine J, Thiart R, Kotze MJ.

S Afr Med J. 2001 Dec;91(12):1053-9.

PubMed [citation]

PMID:: 11845603

See all PubMed Citations (16)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295340.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (5)
2	not provided	1	not provided	not provided	literature only	PubMed (5)
3	not provided	1	not provided	not provided	literature only	PubMed (5)
4	not provided	1	not provided	not provided	literature only	PubMed (5)

Description

Re-evaluation of ACMG classification, scoring: PM2, PS4_supporting, PP4. PP3 could not be scored as the score of 0.718 is below the threshold of >0.75. At least 5 unrelated cases of confirmed FH carry this variant. Many further cases have been reported, however, the classification of their diagnosis is not well defined, so PS4 moderate or strong could not be scored.

#	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
3	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001736482.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This missense variant replaces asparagine with lysine at codon 428 of the LDLR protein. This variant is also known as p.Asn407Lys in the mature protein. This variant alters a conserved asparagine residue in the LDLR type B repeat 1 of the LDLR protein (a.a. 397-438), where pathogenic missense variants are found enriched (ClinVar-LDLR). Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 heterozygous individuals affected with familial hypercholesterolemia (PMID: 11005141, 11668640, 11845603, 11857755, 14508510, 15556094, 21382890, 35047021, 36499307). This variant has also been observed in compound heterozygous state with known pathogenic LDLR variants in two individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 36980993; Callis 2000 dissertation, University of the Orange Free State). It has been shown that this variant segregates with disease in multiple heterozygous affected relatives in one family (Callis 2000 dissertation, University of the Orange Free State). This variant has been detected in over 30 Dutch individuals showing modest severity of hypercholesterolemia with mean LDL-C levels in the 75-88th percentile according to the Dutch Lipid Clinic Network criteria (Hartgers 2020 dissertation, University of Amsterdam). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely 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, SCV002284046.3

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

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 428 of the LDLR protein (p.Asn428Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant familial hypercholesterolemia (PMID: 11005141, 11238294, 11668640, 11857755; Invitae). This variant is also known as N407K. ClinVar contains an entry for this variant (Variation ID: 251766). 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. 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005205210.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: LDLR c.1284C>G (p.Asn428Lys; also known as N407K in the literature) results in a non-conservative amino acid change located in the LDLR class B repeat (IPR000033) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251288 control chromosomes (gnomAD). c.1284C>G has been reported in the literature in both heterozygous and compound heterozygous individuals affected with familial hypercholesterolemia (FH; example: Bunn_2002, Khoo_2000, Razman_2022, Reijman_2023, Rimbert_2022, Sjouke_2015). The variant was also reported to co-occur with another pathogenic APOB variant in an individual who was affected with both FH and familial defective apolipoprotein B-100. This individual had a more severe phenotype than her siblings who carried only one variant (Tai_2001). 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. The following publications have been ascertained in the context of this evaluation (PMID: 36499307, 36752612, 11005141, 11857755, 35047021, 27919364, 11238294). ClinVar contains an entry for this variant (Variation ID: 251766). Based on the evidence outlined above, the variant was classified as likely 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: Nov 10, 2024

ClinVar

Relating variation to medicine