NM_000527.5(LDLR):c.344G>A (p.Arg115His) AND Familial hypercholesterolemia

Germline classification:: Conflicting classifications of pathogenicity (3 submissions)
Last evaluated:: Oct 21, 2021
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:: RCV000771221.12

Allele description [Variation Report for NM_000527.5(LDLR):c.344G>A (p.Arg115His)]

NM_000527.5(LDLR):c.344G>A (p.Arg115His)

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.344G>A (p.Arg115His)

Other names:

FH Fukuoka; NM_000527.5(LDLR):c.344G>A

HGVS:

NC_000019.10:g.11105250G>A
NG_009060.1:g.20870G>A
NM_000527.5:c.344G>AMANE SELECT
NM_001195798.2:c.344G>A
NM_001195799.2:c.221G>A
NM_001195800.2:c.314-2142G>A
NM_001195803.2:c.314-1315G>A
NP_000518.1:p.Arg115His
NP_000518.1:p.Arg115His
NP_001182727.1:p.Arg115His
NP_001182728.1:p.Arg74His
LRG_274t1:c.344G>A
LRG_274:g.20870G>A
LRG_274p1:p.Arg115His
NC_000019.9:g.11215926G>A
NM_000527.4:c.344G>A
c.344G>A

Protein change:

R115H

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000052; dbSNP: rs201102461

NCBI 1000 Genomes Browser:

rs201102461

Molecular consequence:

NM_001195800.2:c.314-2142G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1315G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.344G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.221G>A - 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
SCV000903315	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Mar 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001225051	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 21, 2021)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 9399845, 11005141, 12417285, 15359125, 18718593, 28502495, 28932795, 29399563, 12837857, 27821657, 28492532
SCV001456140	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

SCV000903315

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Mar 1, 2021)

germline

clinical testing

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

SCV001225051

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 21, 2021)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001456140

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

LDLR Database (second edition): new additions to the database and the software, and results of the first molecular analysis.

Varret M, Rabés JP, Thiart R, Kotze MJ, Baron H, Cenarro A, Descamps O, Ebhardt M, Hondelijn JC, Kostner GM, Miyake Y, Pocovi M, Schmidt H, Schuster H, Stuhrmann M, Yamamura T, Junien C, Béroud C, Boileau C.

Nucleic Acids Res. 1998 Jan 1;26(1):248-52.

PubMed [citation]

PMID:: 9399845
PMCID:: PMC147253

See all PubMed Citations (12)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000903315.3

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001225051.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine with histidine at codon 115 of the LDLR protein (p.Arg115His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs201102461, ExAC 0.2%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9399845, 11005141, 12417285, 15359125, 18718593, 28502495, 28932795, 29399563). This variant is also known as R94H. ClinVar contains an entry for this variant (Variation ID: 225402). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on LDLR function (PMID: 12837857, 27821657). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been 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., SCV001456140.1

#	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: Feb 25, 2025

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