NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Apr 28, 2023
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000237461.6

Allele description [Variation Report for NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)]

NM_000527.5(LDLR):c.440C>T (p.Thr147Ile)

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.440C>T (p.Thr147Ile)

Other names:

NM_000527.5(LDLR):c.440C>T; p.Thr147Ile

HGVS:

NC_000019.10:g.11105346C>T
NG_009060.1:g.20966C>T
NM_000527.5:c.440C>TMANE SELECT
NM_001195798.2:c.440C>T
NM_001195799.2:c.317C>T
NM_001195800.2:c.314-2046C>T
NM_001195803.2:c.314-1219C>T
NP_000518.1:p.Thr147Ile
NP_000518.1:p.Thr147Ile
NP_001182727.1:p.Thr147Ile
NP_001182728.1:p.Thr106Ile
LRG_274t1:c.440C>T
LRG_274:g.20966C>T
LRG_274p1:p.Thr147Ile
NC_000019.9:g.11216022C>T
NM_000527.4:c.440C>T
c.440C>T
p.(Thr147Ile)

Protein change:

T106I

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000314; dbSNP: rs879254524

NCBI 1000 Genomes Browser:

rs879254524

Molecular consequence:

NM_001195800.2:c.314-2046C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-1219C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.440C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.440C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.317C>T - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294710	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000599332	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 1, 2016)	germline, not applicable	curation, literature only	PubMed (2) [See all records that cite these PMIDs] 25741868, 21865347
SCV001653593	Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 24, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 21865347, 25741868
SCV003932171	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 6, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004022432	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Apr 28, 2023)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

An improved method on stimulated T-lymphocytes to functionally characterize novel and known LDLR mutations.

Romano M, Di Taranto MD, Mirabelli P, D'Agostino MN, Iannuzzi A, Marotta G, Gentile M, Raia M, Di Noto R, Del Vecchio L, Rubba P, Fortunato G.

J Lipid Res. 2011 Nov;52(11):2095-100. doi: 10.1194/jlr.D017772. Epub 2011 Aug 24.

PubMed [citation]

PMID:: 21865347
PMCID:: PMC3196240

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

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294710.2

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

#	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

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599332.1

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

Description

"Assay Description:Htz patients' Epstein-Barr virus transformed lymphocytes, FACS assays"

PubMed [ID: 21865347]

#	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
2	not applicable	not applicable	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, SCV001653593.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	3	not provided	not provided	clinical testing	PubMed (2)

Description

Reduced activity in functional assays.

#	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		3	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV003932171.1

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

Description

PS3, PM2, PS4_Moderate, PP3

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV004022432.1

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

Description

The NM_000527.5(LDLR):c.440C>T (p.Thr147Ile) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes PS3_Supporting, PM1, PM2, and PP3 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PS3_Supporting: Level 3 assays: PMID 21865347: Htz Patient lymphocytes, FACS assays - results - 55-70% LDLR activity ---- results are below 85% of wild-type activity. So PS3_Supporting is met. PM1: Variant meets PM2 and is on exon 4. So PM1 is met. PM2: This variant is absent from gnomAD (gnomAD v2.1.1). So PM2 is met. PP3: REVEL = 0.811. It is above 0.75, so PP3 is met.

#	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: Jan 13, 2025

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