NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 24, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001339707.8

Allele description [Variation Report for NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu)]

NM_000527.5(LDLR):c.1721G>T (p.Arg574Leu)

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.1721G>T (p.Arg574Leu)

Other names:

NM_000527.5(LDLR):c.1721G>T

HGVS:

NC_000019.10:g.11116874G>T
NG_009060.1:g.32494G>T
NM_000527.5:c.1721G>TMANE SELECT
NM_001195798.2:c.1721G>T
NM_001195799.2:c.1598G>T
NM_001195800.2:c.1217G>T
NM_001195803.2:c.1340G>T
NP_000518.1:p.Arg574Leu
NP_000518.1:p.Arg574Leu
NP_001182727.1:p.Arg574Leu
NP_001182728.1:p.Arg533Leu
NP_001182729.1:p.Arg406Leu
NP_001182732.1:p.Arg447Leu
LRG_274t1:c.1721G>T
LRG_274:g.32494G>T
NC_000019.9:g.11227550G>T
NM_000527.4(LDLR):c.1721G>T
NM_000527.4:c.1721G>T
c.1721G>T

Protein change:

R406L

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001502; dbSNP: rs777188764

NCBI 1000 Genomes Browser:

rs777188764

Molecular consequence:

NM_000527.5:c.1721G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1721G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1598G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1217G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1340G>T - 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
SCV001533471	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 29, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22698793, 28492532
SCV004358542	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 24, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 2506357, 22698793, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001533471

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 29, 2016)

germline

clinical testing

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

SCV004358542

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 24, 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

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

Relationships of the chromosomal species in the Eurasian mole rats of the Spalax ehrenbergi group as determined by DNA-DNA hybridization, and an estimate of the spalacid-murid divergence time.

Catzeflis FM, Nevo E, Ahlquist JE, Sibley CG.

J Mol Evol. 1989 Sep;29(3):223-32.

PubMed [citation]

PMID:: 2506357

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001533471.4

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

Description

In summary, this is a novel missense change with uncertain impact on protein function that has been reported in one patient. However, the clinical significance of this finding is still unknown. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant has been reported in an individual affected with hypercholesterolemia. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 22698793). This variant is present in population databases (rs777188764, ExAC 0.02%). This sequence change replaces arginine with leucine at codon 574 of the LDLR protein (p.Arg574Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine.

#	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, SCV004358542.1

#	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.Arg553Leu in the mature protein) replaces arginine with leucine at codon 574 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 a few individuals affected with familial hypercholesterolemia (PMID: 22698793; ClinVar SCV002506357.1). This variant has been identified in 4/251472 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Arg574His and p.Arg574Cys, are considered to be disease-causing (ClinVar variation ID: 251996 and 183123), suggesting that arginine at this position is important for LDLR protein function. 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

Last Updated: Oct 13, 2024

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