NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 8, 2024
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:: RCV001057854.14

Allele description [Variation Report for NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr)]

NM_000527.5(LDLR):c.2050G>A (p.Ala684Thr)

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.2050G>A (p.Ala684Thr)

HGVS:

NC_000019.10:g.11120432G>A
NG_009060.1:g.36052G>A
NM_000527.5:c.2050G>AMANE SELECT
NM_001195798.2:c.2050G>A
NM_001195799.2:c.1927G>A
NM_001195800.2:c.1546G>A
NM_001195803.2:c.1606+199G>A
NP_000518.1:p.Ala684Thr
NP_000518.1:p.Ala684Thr
NP_001182727.1:p.Ala684Thr
NP_001182728.1:p.Ala643Thr
NP_001182729.1:p.Ala516Thr
LRG_274t1:c.2050G>A
LRG_274:g.36052G>A
LRG_274p1:p.Ala684Thr
NC_000019.9:g.11231108G>A
NM_000527.4:c.2050G>A
c.2050G>A

Protein change:

A516T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000754; dbSNP: rs774730452

NCBI 1000 Genomes Browser:

rs774730452

Molecular consequence:

NM_001195803.2:c.1606+199G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2050G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2050G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1927G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1546G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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PRTN3 proteinase 3 [Homo sapiens]
PRTN3 proteinase 3 [Homo sapiens]
Gene ID:5657

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Gene Links for GEO Profiles (Select 86136185) (1)
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Gene Links for Nucleotide (Select 2131675128) (1000)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001222369	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 11005141, 28492532
SCV001347392	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11005141, 26608663, 25741868
SCV002086861	Natera, Inc.	no assertion criteria provided	Uncertain significance (Feb 10, 2020)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001222369

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001347392

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV002086861

Natera, Inc.

no assertion criteria provided

Uncertain significance
(Feb 10, 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

Low-density lipoprotein receptor gene mutations in a Southeast Asian population with familial hypercholesterolemia.

Khoo KL, van Acker P, Defesche JC, Tan H, van de Kerkhof L, Heijnen-van Eijk SJ, Kastelein JJ, Deslypere JP.

Clin Genet. 2000 Aug;58(2):98-105.

PubMed [citation]

PMID:: 11005141

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001222369.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 684 of the LDLR protein (p.Ala684Thr). This variant is present in population databases (rs774730452, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 11005141; Invitae). This variant is also known as A663T. ClinVar contains an entry for this variant (Variation ID: 252192). 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%. 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001347392.4

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

Description

This missense variant (also known as p.Ala663Thr in the mature protein) replaces alanine with threonine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 11005141, 26608663). This variant has been identified in 4/251258 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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., SCV002086861.1

#	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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