NM_000527.5(LDLR):c.398A>C (p.Asp133Ala) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 15, 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:: RCV000700653.10

Allele description [Variation Report for NM_000527.5(LDLR):c.398A>C (p.Asp133Ala)]

NM_000527.5(LDLR):c.398A>C (p.Asp133Ala)

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.398A>C (p.Asp133Ala)

HGVS:

NC_000019.10:g.11105304A>C
NG_009060.1:g.20924A>C
NM_000527.5:c.398A>CMANE SELECT
NM_001195798.2:c.398A>C
NM_001195799.2:c.275A>C
NM_001195800.2:c.314-2088A>C
NM_001195803.2:c.314-1261A>C
NP_000518.1:p.Asp133Ala
NP_000518.1:p.Asp133Ala
NP_001182727.1:p.Asp133Ala
NP_001182728.1:p.Asp92Ala
LRG_274t1:c.398A>C
LRG_274:g.20924A>C
LRG_274p1:p.Asp133Ala
NC_000019.9:g.11215980A>C
NM_000527.4:c.398A>C

Protein change:

D133A

Links:

dbSNP: rs1317204420

NCBI 1000 Genomes Browser:

rs1317204420

Molecular consequence:

NM_001195800.2:c.314-2088A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1261A>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.398A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.398A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.275A>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
SCV000829417	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 15, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001456142	Natera, Inc.	no assertion criteria provided	Uncertain significance (Sep 16, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000829417

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 15, 2023)

germline

clinical testing

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

SCV001456142

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Sep 16, 2020)

germline

clinical testing

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829417.6

#	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 aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 133 of the LDLR protein (p.Asp133Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with LDLR-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 577814). 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. 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

From Natera, Inc., SCV001456142.1

#	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

Last Updated: Sep 29, 2024

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