NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 25, 2022
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:: RCV001284641.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)]

NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn)

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.1735G>A (p.Asp579Asn)

Other names:

FH Cincinnati-4

HGVS:

NC_000019.10:g.11116888G>A
NG_009060.1:g.32508G>A
NM_000527.5:c.1735G>AMANE SELECT
NM_001195798.2:c.1735G>A
NM_001195799.2:c.1612G>A
NM_001195800.2:c.1231G>A
NM_001195803.2:c.1354G>A
NP_000518.1:p.Asp579Asn
NP_000518.1:p.Asp579Asn
NP_001182727.1:p.Asp579Asn
NP_001182728.1:p.Asp538Asn
NP_001182729.1:p.Asp411Asn
NP_001182732.1:p.Asp452Asn
LRG_274t1:c.1735G>A
LRG_274:g.32508G>A
LRG_274p1:p.Asp579Asn
NC_000019.9:g.11227564G>A
NM_000527.4:c.1735G>A
P01130:p.Asp579Asn
c.1735G>A

Protein change:

D411N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001510; UniProtKB: P01130#VAR_005402; dbSNP: rs875989929

NCBI 1000 Genomes Browser:

rs875989929

Molecular consequence:

NM_000527.5:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1735G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1612G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1231G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1354G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001470530	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Oct 21, 2019)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 28965616, 16542394, 11585102, 11373616, 10532689, 7635461, 1301956, 31401775, 29874871, 26467025
SCV002513146	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 25, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001470530

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Oct 21, 2019)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV002513146

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 25, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study.

Pirillo A, Garlaschelli K, Arca M, Averna M, Bertolini S, Calandra S, Tarugi P, Catapano AL; LIPIGEN Group..

Atheroscler Suppl. 2017 Oct;29:17-24. doi: 10.1016/j.atherosclerosissup.2017.07.002.

PubMed [citation]

PMID:: 28965616

Molecular genetic analysis of 1053 Danish individuals with clinical signs of familial hypercholesterolemia.

Brusgaard K, Jordan P, Hansen H, Hansen AB, Hørder M.

Clin Genet. 2006 Mar;69(3):277-83.

PubMed [citation]

PMID:: 16542394

See all PubMed Citations (10)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470530.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

Not found in the gnomAD exomes dataset, and the data is high quality. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002513146.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies show that cultured fibroblasts from a patient with p.(D579N) and another unknown LDLR variant had <2% LDLR activity (Hobbs et al., 1992); however, the p.(D579N) variant was not studied in isolation and its functional effect in vivo is unknown; Also known as D558N, FH-Cincinnati-4; This variant is associated with the following publications: (PMID: 10532689, 11373616, 28965616, 7635461, 34037665, 31447099, 29874871, 31689621, 31401775, 11585102, 1301956, 16542394, 33955087)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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