NM_000527.5(LDLR):c.1735G>A (p.Asp579Asn) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 4, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000825595.4

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]

Observations:

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000966937	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (May 4, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7635461, 1301956, 10532689, 28965616, 16542394, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000966937

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(May 4, 2018)

germline

clinical testing

PubMed (6)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

An efficient screening procedure detecting six novel mutations in the LDL receptor gene in Swedish children with hypercholesterolemia.

Ekström U, Abrahamson M, Sveger T, Lombardi P, Nilsson-Ehle P.

Hum Genet. 1995 Aug;96(2):147-50.

PubMed [citation]

PMID:: 7635461

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

See all PubMed Citations (6)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000966937.1

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

Description

The p.Asp579Asn variant (also known as p.Asp558Asn, FH-Cinncinatti-4) in LDLR ha s been reported in 7 individuals with hypercholesterolemia (5 heterozygous, 1 do uble heterozygote with the p.Arg3527Gln variant in APOB, and one individual desc ribed by the authors as "compound heterozygote with an unidentified second varia nt"; Hobbs 1992, Ekstrom 1995, Jensen 1999, Brusgaard 2006, Pirillo 2017). This variant was absent from large population studies and is reported in ClinVar (Var iation ID: 252006). In vitro functional studies provide some evidence that the p .Asp5789Asn variant may result in transport defects and ER retention of the LDL receptor (Hobbs 1992). However, these types of assays may not accurately represe nt biological function. Computational prediction tools and conservation analysis suggest that the p.Asp579Asn variant may impact the protein, though this inform ation is not predictive enough to determine pathogenicity. A different variant a t the same residue (p.Asp579Tyr) has been identified in >15 Italian individuals with hypercholesterolemia, suggesting change at this position may not be tolerat ed (Bertolini 2000). In summary, although additional studies are required to ful ly establish its clinical significance, the p.Asp579Asn variant is likely pathog enic. ACMG/AMP Criteria applied: PM2; PM5; PS4_Moderate; PP3; PS3_Supporting.

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

Last Updated: Sep 29, 2024

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