NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (8 submissions)
Last evaluated:: Dec 18, 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:: RCV000237883.28

Allele description [Variation Report for NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)]

NM_000527.5(LDLR):c.1414G>T (p.Asp472Tyr)

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.1414G>T (p.Asp472Tyr)

HGVS:

NC_000019.10:g.11113590G>T
NG_009060.1:g.29210G>T
NM_000527.5:c.1414G>TMANE SELECT
NM_001195798.2:c.1414G>T
NM_001195799.2:c.1291G>T
NM_001195800.2:c.910G>T
NM_001195803.2:c.1033G>T
NP_000518.1:p.Asp472Tyr
NP_000518.1:p.Asp472Tyr
NP_001182727.1:p.Asp472Tyr
NP_001182728.1:p.Asp431Tyr
NP_001182729.1:p.Asp304Tyr
NP_001182732.1:p.Asp345Tyr
LRG_274t1:c.1414G>T
LRG_274:g.29210G>T
LRG_274p1:p.Asp472Tyr
NC_000019.9:g.11224266G>T
NM_000527.4:c.1414G>T
NM_000527.5:c.1414G>T
c.1414G>T
p.(Asp472Tyr)
p.D472Y

Protein change:

D304Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000886; dbSNP: rs730882102

NCBI 1000 Genomes Browser:

rs730882102

Molecular consequence:

NM_000527.5:c.1414G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1414G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1291G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.910G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1033G>T - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

functional variant [Sequence Ontology: SO:0001536] - Comment(s)

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

Recent activity

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PREDICTED: Zea mays carbohydrate transporter/ sugar porter/ transporter (LOC1001...
PREDICTED: Zea mays carbohydrate transporter/ sugar porter/ transporter (LOC100192005), transcript variant X1, mRNA
gi|1897959868|ref|XM_020547362.3|

Nucleotide
hypothetical protein PAGK_1992 [Cutibacterium acnes HL096PA1]
hypothetical protein PAGK_1992 [Cutibacterium acnes HL096PA1]
gi|481321483|gnl|mmpucla|PAGK_1992| J80794.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295416	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17196209, 21310417 Citation Link,
SCV000540817	Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation See additional submitters Centre of Molecular Biology and Gene Therapy, University Hospital Brno	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 5, 2016)	inherited	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25741868, 22698793
SCV000606418	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV001653634	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 24, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17196209, 23375686, 25487149, 25647241, 31447099, 32977124, 31980526, 25741868
SCV002022657	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003920885	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004820314	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Dec 18, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 17196209, 21310417, 22698793, 23375686, 25647241, 27542166, 28008010, 35101175, 37129685, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	2602	not provided	clinical testing, literature only
not provided	germline	unknown	7	not provided	not provided	108544	not provided	clinical testing, research
Caucasian	inherited	yes	11	10	not provided	3964	yes	clinical testing
Caucasian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.

Do R, Stitziel NO, Won HH, Jørgensen AB, Duga S, Angelica Merlini P, Kiezun A, Farrall M, Goel A, Zuk O, Guella I, Asselta R, Lange LA, Peloso GM, Auer PL; NHLBI Exome Sequencing Project., Girelli D, Martinelli N, Farlow DN, DePristo MA, Roberts R, Stewart AF, et al.

Nature. 2015 Feb 5;518(7537):102-6. doi: 10.1038/nature13917. Epub 2014 Dec 10.

PubMed [citation]

PMID:: 25487149
PMCID:: PMC4319990

Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network.

eMERGE Consortium. Electronic address: agibbs@bcm.edu.; eMERGE Consortium..

Am J Hum Genet. 2019 Sep 5;105(3):588-605. doi: 10.1016/j.ajhg.2019.07.018. Epub 2019 Aug 22.

PubMed [citation]

PMID:: 31447099
PMCID:: PMC6731372

See all PubMed Citations (14)

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295416.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix, SCV000503344.1

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

Description

subject mutated among 2600 FH index cases screened = 1 / Software predictions: Conflicting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	2600	not provided	not provided		1	not provided	not provided	not provided

From Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, SCV000540817.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	11	not provided	yes	clinical testing	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	3964	Whole blood	not provided		11	not provided	10	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606418.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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

From Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II, SCV001653634.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	clinical testing	PubMed (8)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002022657.3

#	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 Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, SCV003920885.1

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

Description

LDLR NM_000527.4 exon 10 p.Asp472Tyr (c.1414G>T): This variant has been reported in the literature in the heterozygous state in several individuals with elevated LDL-C levels and/or a history of myocardial infaction, segregating with disease in multiple affected family members (Campagna 2008 PMID:17196209, Tichy 2012 PMID:22698793, Bertolini 2013 PMID:23375686, Do 2015 PMID:25487149, Thormaehlen 2015 PMID:25647241, Vohnout 2016 PMID:27542166). This variant is also present in 0.01% (5/30612) of South Asian alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/19-11224266-G-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:183116). Evolutionary conservation suggests that this variant may not impact the protein, but computational predictive tools do suggest an impact. In addition, an in vitro functional study predicts that this variant will impact the protein (Thormaehlen 2015 PMID:25647241). However, this study may not accurately represent in vivo biological function. Of note, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, 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

From All of Us Research Program, National Institutes of Health, SCV004820314.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (10)

Description

This missense variant replaces aspartic acid with tyrosine at codon 472 of the LDLR protein. This variant is also known as p.Asp451Tyr in the mature 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). A functional study has demonstrated that the mutant protein is partially defective in LDLR activity due to impaired protein expression or instability (PMID: 25647241). This variant has been reported in over ten individuals affected with familial hypercholesterolemia (PMID: 17196209, 17196209, 21310417, 22698793, 23375686, 27542166, 28008010, 27542166, 28008010, 35101175, 37129685; Fife 2021 https://doi.org/10.1101/2021.08.12.21261563; Alieva 2022, dissertation, University of Milan) and is reported to be associated with mild symptoms. This variant has also been shown to segregate with disease in two families (PMID: 17196209, 27542166). This variant has been identified in 15/282578 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	108544	not provided	not provided		7	not provided	not provided	not provided

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000503344	Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	flagged submission Reason: Older and outlier claim with insufficient supporting evidence Notes: None (ACMG Guidelines, 2015)	Likely benign (Dec 16, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000503344

Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix

flagged submission

Reason: Older and outlier claim with insufficient supporting evidence

Notes: None

(ACMG Guidelines, 2015)

Likely benign
(Dec 16, 2016)

germline

clinical testing

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

Last Updated: Oct 13, 2024

Relating variation to medicine