NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 16, 2024
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:: RCV001381623.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln)]

NM_000527.5(LDLR):c.1217G>A (p.Arg406Gln)

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.1217G>A (p.Arg406Gln)

Other names:

NM_000527.5(LDLR):c.1217G>A

HGVS:

NC_000019.10:g.11113308G>A
NG_009060.1:g.28928G>A
NM_000527.5:c.1217G>AMANE SELECT
NM_001195798.2:c.1217G>A
NM_001195799.2:c.1094G>A
NM_001195800.2:c.713G>A
NM_001195803.2:c.836G>A
NP_000518.1:p.Arg406Gln
NP_000518.1:p.Arg406Gln
NP_001182727.1:p.Arg406Gln
NP_001182728.1:p.Arg365Gln
NP_001182729.1:p.Arg238Gln
NP_001182732.1:p.Arg279Gln
LRG_274t1:c.1217G>A
LRG_274:g.28928G>A
NC_000019.9:g.11223984G>A
NM_000527.4(LDLR):c.1217G>A
NM_000527.4:c.1217G>A
P01130:p.Arg406Gln
c.1217G>A

Protein change:

R238Q

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000650; UniProtKB: P01130#VAR_013954; dbSNP: rs552422789

NCBI 1000 Genomes Browser:

rs552422789

Molecular consequence:

NM_000527.5:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1217G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1094G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.713G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.836G>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
SCV001580100	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10882754, 17094996, 28008010, 8882879, 25461735, 26343872, 28492532
SCV004358515	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 503318, 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580100

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 16, 2024)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004358515

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Sep 26, 2023)

germline

clinical testing

PubMed (10)
[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

Molecular genetics of familial hypercholesterolemia in Israel.

Reshef A, Nissen H, Triger L, Hensen TS, Eliav O, Schurr D, Safadi R, Gare M, Leitersdorf E.

Hum Genet. 1996 Nov;98(5):581-6.

PubMed [citation]

PMID:: 8882879

Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.

Jannes CE, Santos RD, de Souza Silva PR, Turolla L, Gagliardi AC, Marsiglia JD, Chacra AP, Miname MH, Rocha VZ, Filho WS, Krieger JE, Pereira AC.

Atherosclerosis. 2015 Jan;238(1):101-7. doi: 10.1016/j.atherosclerosis.2014.11.009. Epub 2014 Nov 14.

PubMed [citation]

PMID:: 25461735

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001580100.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 406 of the LDLR protein (p.Arg406Gln). This variant is present in population databases (rs552422789, gnomAD 0.007%). This missense change has been observed in individuals with LDLR-related conditions (PMID: 10882754, 17094996, 28008010). ClinVar contains an entry for this variant (Variation ID: 228798). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg406 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8882879, 25461735, 26343872). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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, SCV004358515.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces arginine with glutamine at codon 406 in LDLR type B repeat 1 in EGF precursor homology domain of the LDLR protein. This variant is also known as p.Arg385Gln in the mature 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). Splice site prediction tools suggest that this variant may create a new acceptor site. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in nine unrelated individuals affected with familial hypercholesterolemia (PMID: 10882754, 17094996, 23680767, 28008010, 29353225, 33418990, 34037665, 36499307, ClinVar SCV000503318.1). Different missense variants affecting the same codon, p.Arg406Trp and p.Arg406Pro, are considered to be disease-causing (ClinVar variation ID: 226351 and 226352), suggesting that arginine at this position is important for LDLR protein function. This variant has been identified in 4/251042 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the 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: Sep 29, 2024

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