NM_000527.5(LDLR):c.1215C>G (p.Asn405Lys) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 18, 2019
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:: RCV000791392.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1215C>G (p.Asn405Lys)]

NM_000527.5(LDLR):c.1215C>G (p.Asn405Lys)

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.1215C>G (p.Asn405Lys)

HGVS:

NC_000019.10:g.11113306C>G
NG_009060.1:g.28926C>G
NM_000527.5:c.1215C>GMANE SELECT
NM_001195798.2:c.1215C>G
NM_001195799.2:c.1092C>G
NM_001195800.2:c.711C>G
NM_001195803.2:c.834C>G
NP_000518.1:p.Asn405Lys
NP_000518.1:p.Asn405Lys
NP_001182727.1:p.Asn405Lys
NP_001182728.1:p.Asn364Lys
NP_001182729.1:p.Asn237Lys
NP_001182732.1:p.Asn278Lys
LRG_274t1:c.1215C>G
LRG_274:g.28926C>G
LRG_274p1:p.Asn405Lys
NC_000019.9:g.11223982C>G
NM_000527.4:c.1215C>G
c.1215C>G
p.(Asn405Lys)

Protein change:

N237K

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000537; dbSNP: rs879254837

NCBI 1000 Genomes Browser:

rs879254837

Molecular consequence:

NM_000527.5:c.1215C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1215C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1092C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.711C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.834C>G - 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
SCV000824745	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Nov 22, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001360701	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Nov 18, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9237502, 23833242, 29576406 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824745

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Nov 22, 2018)

germline

clinical testing

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

SCV001360701

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Nov 18, 2019)

germline

clinical testing

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

Citation Link

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

CpG hotspot mutations at the LDL receptor locus are a frequent cause of familial hypercholesterolaemia among South African Indians.

Kotze MJ, Loubser O, Thiart R, de Villiers JN, Langenhoven E, Theart L, Steyn K, Marais AD, Raal FJ.

Clin Genet. 1997 Jun;51(6):394-8.

PubMed [citation]

PMID:: 9237502

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824745.5

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

Description

This sequence change replaces asparagine with lysine at codon 405 of the LDLR protein (p.Asn405Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with¬†hypercholesterolemia, segregating with¬†the disease in a single family (PMID:¬†9237502, 29576406,¬†Invitae). This variant is also known in the literature as p.Asn384Lys. ClinVar contains an entry for this variant (Variation ID: 251738). This variant is not present in population databases (ExAC no frequency).

#	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, SCV001360701.1

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

Description

Variant summary: LDLR c.1215C>G (p.Asn405Lys) results in a non-conservative amino acid change in 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 251046 control chromosomes (gnomAD). c.1215C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and was stated to segregate with disease in at least one family (Hernandez Flores_2018, Kotze_1997, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite 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

Last Updated: Sep 29, 2024

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