NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 28, 2024
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:: RCV000775087.12

Allele description [Variation Report for NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn)]

NM_000527.5(LDLR):c.2098G>A (p.Asp700Asn)

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.2098G>A (p.Asp700Asn)

Other names:

NM_000527.5(LDLR):c.2098G>A

HGVS:

NC_000019.10:g.11120480G>A
NG_009060.1:g.36100G>A
NM_000527.5:c.2098G>AMANE SELECT
NM_001195798.2:c.2098G>A
NM_001195799.2:c.1975G>A
NM_001195800.2:c.1594G>A
NM_001195803.2:c.1606+247G>A
NP_000518.1:p.Asp700Asn
NP_000518.1:p.Asp700Asn
NP_001182727.1:p.Asp700Asn
NP_001182728.1:p.Asp659Asn
NP_001182729.1:p.Asp532Asn
LRG_274t1:c.2098G>A
LRG_274:g.36100G>A
LRG_274p1:p.Asp700Asn
NC_000019.9:g.11231156G>A
NM_000527.3:c.2098G>A
NM_000527.4:c.2098G>A
c.2098G>A
p.ASP700ASN
p.D700N

Protein change:

D532N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001602; dbSNP: rs375009082

NCBI 1000 Genomes Browser:

rs375009082

Molecular consequence:

NM_001195803.2:c.1606+247G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2098G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2098G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1975G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1594G>A - 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
SCV000909191	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 25, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15199436, 23669246, 28008010, 34869944, 25741868
SCV001461326	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing
SCV002511537	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Dec 19, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 15199436, 19118540, 23669246, 25487149, 28964736, 32906206, 32041611, 32466883, 34869944 Citation Link,
SCV003292778	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 28, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 15199436, 19118540, 23669246, 34869944, 22353362, 32015373, 34456049, 28492532

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

Genetic identification of familial hypercholesterolemia within a single U.S. health care system.

Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, Barr ML, Giovanni MA, Ritchie MD, Overton JD, Reid JG, Metpally RP, Wardeh AH, Borecki IB, Yancopoulos GD, Baras A, Shuldiner AR, Gottesman O, et al.

Science. 2016 Dec 23;354(6319). doi:pii: aaf7000. 10.1126/science.aaf7000.

PubMed [citation]

PMID:: 28008010

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (15)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909191.5

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

Description

This missense variant (also known as p.Asp679Asn in the mature protein) replaces aspartic acid with asparagine at codon 700 in the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant causes a significant decrease in LDLR uptake (PMID: 34869944). This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15199436, 23669246, 28008010; Color internal data). This variant has been identified in 8/282422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). This variant is classified as likely pathogenic by the ClinGen Familial Hypercholesterolemia VCEP (ClinVar variation ID: 200923). Additionally, a different variant occurring at the same codon, p.Asp700Gly, is considered to be disease-causing (Clinvar variation ID: 252220), indicating that aspartic acid at this position is important for LDLR protein function. 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 Natera, Inc., SCV001461326.1

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002511537.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: LDLR c.2098G>A (p.Asp700Asn) results in a conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251024 control chromosomes (gnomAD). The variant, c.2098G>A, has been reported in the literature in multiple individuals affected with (familial) hypercholesterolemia (e.g. Leren_2004, Laurie_2009, Futema_2013, Defesche_2017, Trinder_2020, Dron_2020), however, it was also found in controls (Do_2015, Narang_2020). These data indicate that the variant maybe associated with disease. A recent publication reported experimental evidence evaluating an impact on protein function, and demonstrated a decreased LDLR activity (~20% of normal) in an in vitro expression system (Larrea-Sebal_2021). Seven other submitters, including a variant curation expert panel (ClinGen), have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as VUS (n=5), while ClinGen classified it as likely pathogenic. 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003292778.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 700 of the LDLR protein (p.Asp700Asn). This variant is present in population databases (rs375009082, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 15199436, 19118540, 23669246; Invitae). This variant is also known as p.D679N. ClinVar contains an entry for this variant (Variation ID: 200923). 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%. Experimental studies have shown that this missense change affects LDLR function (PMID: 34869944). This variant disrupts the p.Asn700 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22353362, 32015373, 34456049; Invitae), which suggests that this may be a clinically significant amino acid residue. 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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