NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Oct 22, 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:: RCV001183695.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)]

NM_000527.5(LDLR):c.1049G>C (p.Arg350Pro)

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.1049G>C (p.Arg350Pro)

Other names:

FH Alghero; NM_000527.5(LDLR):c.1049G>C

HGVS:

NC_000019.10:g.11110760G>C
NG_009060.1:g.26380G>C
NM_000527.5:c.1049G>CMANE SELECT
NM_001195798.2:c.1049G>C
NM_001195799.2:c.926G>C
NM_001195800.2:c.545G>C
NM_001195803.2:c.668G>C
NP_000518.1:p.Arg350Pro
NP_000518.1:p.Arg350Pro
NP_001182727.1:p.Arg350Pro
NP_001182728.1:p.Arg309Pro
NP_001182729.1:p.Arg182Pro
NP_001182732.1:p.Arg223Pro
LRG_274t1:c.1049G>C
LRG_274:g.26380G>C
LRG_274p1:p.Arg350Pro
NC_000019.9:g.11221436G>C
NM_000527.4:c.1049G>C
P01130:p.Arg350Pro
c.1049G>C

Protein change:

R182P

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001337; UniProtKB: P01130#VAR_005368; dbSNP: rs875989914

NCBI 1000 Genomes Browser:

rs875989914

Molecular consequence:

NM_000527.5:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1049G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.926G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.545G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.668G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia (FH)
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
SCV000627011	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 22, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9026534, 19837725, 15100232, 31106925, 28492532
SCV001349491	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 7, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9026534, 15100232, 31106925, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000627011

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 22, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001349491

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 7, 2022)

germline

clinical testing

PubMed (4)
[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

Development of a high-resolution melting method for mutation detection in familial hypercholesterolaemia patients.

Whittall RA, Scartezini M, Li K, Hubbart C, Reiner Z, Abraha A, Neil HA, Dedoussis G, Humphries SE.

Ann Clin Biochem. 2010 Jan;47(Pt 1):44-55. doi: 10.1258/acb.2009.009076. Epub 2009 Oct 16.

PubMed [citation]

PMID:: 19837725

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

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000627011.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 350 of the LDLR protein (p.Arg350Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9026534, 19837725; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 226343). 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. Experimental studies have shown that this missense change affects LDLR function (PMID: 15100232). This variant disrupts the p.Arg350 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 31106925), which suggests that this may be a clinically significant amino acid residue. 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 Color Diagnostics, LLC DBA Color Health, SCV001349491.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This missense variant (also known as p.Arg329Pro in the mature protein) replaces arginine with proline at codon 350 in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Experimental functional studies have shown that this variant causes LDLR protein misfolding and significant reduction in protein activity (PMID: 9026534, 15100232). This variant has been reported in one individual affected with familial hypercholesterolemia (PMID: 31106925). This variant has also been reported in compound heterozygosity with a pathogenic variant p.Cys248Tyr in an individual affected with familial hypercholesterolemia (PMID: 9026534). The proband's affected sister was also compound heterozygous. The proband's affected father was heterozygous for this variant, and the proband's affected mother was heterozygous for p.Cys248Tyr (PMID: 9026534). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). In summary, this rare variant has been shown to disrupt LDLR function and demonstrated to segregate with disease in a family study. Based on available evidence, this variant is 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

Last Updated: Jun 23, 2024

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