NM_000527.5(LDLR):c.1298A>C (p.Asp433Ala) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 22, 2023
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:: RCV002755705.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1298A>C (p.Asp433Ala)]

NM_000527.5(LDLR):c.1298A>C (p.Asp433Ala)

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.1298A>C (p.Asp433Ala)

HGVS:

NC_000019.10:g.11113389A>C
NG_009060.1:g.29009A>C
NM_000527.5:c.1298A>CMANE SELECT
NM_001195798.2:c.1298A>C
NM_001195799.2:c.1175A>C
NM_001195800.2:c.794A>C
NM_001195803.2:c.917A>C
NP_000518.1:p.Asp433Ala
NP_000518.1:p.Asp433Ala
NP_001182727.1:p.Asp433Ala
NP_001182728.1:p.Asp392Ala
NP_001182729.1:p.Asp265Ala
NP_001182732.1:p.Asp306Ala
LRG_274t1:c.1298A>C
LRG_274:g.29009A>C
LRG_274p1:p.Asp433Ala
NC_000019.9:g.11224065A>C
NM_000527.4:c.1298A>C

Protein change:

D265A

Molecular consequence:

NM_000527.5:c.1298A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1298A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1175A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.794A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.917A>C - 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
SCV003016789	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Mar 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 1446662, 31491741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003016789

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Mar 22, 2023)

germline

clinical testing

PubMed (3)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A point mutation of low-density-lipoprotein receptor causing rapid degradation of the receptor.

Miyake Y, Tajima S, Funahashi T, Yamamura T, Yamamoto A.

Eur J Biochem. 1992 Nov 15;210(1):1-7.

PubMed [citation]

PMID:: 1446662

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.

Hori M, Ohta N, Takahashi A, Masuda H, Isoda R, Yamamoto S, Son C, Ogura M, Hosoda K, Miyamoto Y, Harada-Shiba M.

Atherosclerosis. 2019 Oct;289:101-108. doi: 10.1016/j.atherosclerosis.2019.08.004. Epub 2019 Aug 19.

PubMed [citation]

PMID:: 31491741

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003016789.2

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

Description

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. This variant disrupts the p.Asp433 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1446662, 31491741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 433 of the LDLR protein (p.Asp433Ala).

#	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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