NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (4 submissions)
Last evaluated:: Feb 10, 2022
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:: RCV000238087.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys)]

NM_000527.5(LDLR):c.1856T>G (p.Phe619Cys)

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.1856T>G (p.Phe619Cys)

Other names:

NM_000527.5(LDLR):c.1856T>G; p.Phe619Cys

HGVS:

NC_000019.10:g.11120102T>G
NG_009060.1:g.35722T>G
NM_000527.5:c.1856T>GMANE SELECT
NM_001195798.2:c.1856T>G
NM_001195799.2:c.1733T>G
NM_001195800.2:c.1352T>G
NM_001195803.2:c.1475T>G
NP_000518.1:p.Phe619Cys
NP_000518.1:p.Phe619Cys
NP_001182727.1:p.Phe619Cys
NP_001182728.1:p.Phe578Cys
NP_001182729.1:p.Phe451Cys
NP_001182732.1:p.Phe492Cys
LRG_274t1:c.1856T>G
LRG_274:g.35722T>G
LRG_274p1:p.Phe619Cys
NC_000019.9:g.11230778T>G
NM_000527.4:c.1856T>G
c.1856T>G

Protein change:

F451C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001535; dbSNP: rs879255054

NCBI 1000 Genomes Browser:

rs879255054

Molecular consequence:

NM_000527.5:c.1856T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1856T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1733T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1352T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1475T>G - 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

Recent activity

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Saxifraga subsessiliflora voucher Supplementary Expedition Team to Qinghai-Tibet...
Saxifraga subsessiliflora voucher Supplementary Expedition Team to Qinghai-Tibet (KUN) trnL(UAA) gene and trnL-trnF intergenic spacer, partial sequence; chloroplast
gi|998152014|gb|KU524439.1|

Nucleotide
Saxifraga geranioides x Saxifraga pubescens subsp. iratiana isolate Spg1_1728xg-...
Saxifraga geranioides x Saxifraga pubescens subsp. iratiana isolate Spg1_1728xg-1 trnL-rpl32 intergenic spacer, complete sequence; ribosomal protein L32 (rpl32) gene, complete cds; and rpl32-ndhF intergenic spacer, complete sequence; chloroplast
gi|2431123527|gb|OP823100.1|

Nucleotide
Mus musculus Ly49J gene, intron 1 and exon 2, partial sequence; and partial cds
Mus musculus Ly49J gene, intron 1 and exon 2, partial sequence; and partial cds
gi|14009606|gb|AF294736.1|

Nucleotide
Mus musculus strain 129 Ly49i1 gene, exons 3 and 4 and partial cds
Mus musculus strain 129 Ly49i1 gene, exons 3 and 4 and partial cds
gi|18699272|gb|AF425095.1|

Nucleotide
putative protein kinase [Arabidopsis thaliana]
putative protein kinase [Arabidopsis thaliana]
gi|20198014|gnl|TIGR|At2g40270|gb|A 62.2|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295717	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,
SCV000583897	U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000606543	Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	no assertion criteria provided	Pathogenic	germline	research
SCV002506394	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely pathogenic (Feb 10, 2022)	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	unknown	not provided	not provided	not provided	not provided	not provided	research, curation
not provided	germline	yes	4	1	not provided	1	not provided	clinical testing, literature only

Citations

PubMed

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Fouchier SW, Kastelein JJ, Defesche JC.

Hum Mutat. 2005 Dec;26(6):550-6.

PubMed [citation]

PMID:: 16250003

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, SCV000295717.2

#	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 U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille, SCV000583897.1

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

Description

Dutch Lipid Clinic Scoring : Definite FH

#	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	1	not provided

From Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum, SCV000606543.1

#	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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506394.1

#	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.1856T>G (p.Phe619Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PP4, PS4_Supporting, PP1) 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: PM2 Met: This variant is absent in gnomAD (gnomAD v2.1.1). PP3 Met: REVEL = 0.856, which is above the threshold of 0.75. PP4 Met: This variant meets PM2 and is identified >1 index cases who met clinical criteria for FH after alternative causes for high cholesterol were excluded. PS4_Supporting Met: Variant meets PM2, and is identified in 2 unrelated index cases who fulfil DLCN criteria for FH diagnosis from different labs. One index case is from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1), another index case is reported from Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands (PMID16250003, SCV000295717.2). PP1 Met: Variant segregates with FH phenotype in 2 informative meiosis in one family reported from U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille (SCV000583897.1). There are two other variants in same codon: LDLR: NM_000527:c.1855T>C (p.Phe619Leu), LDLR: NM_000527:c.1856T>C (p.Phe619Ser), which are classified as Likely Pathogenic by these guidelines. Neither variant is classified as Pathogenic, therefore PM5 is not 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: Jun 23, 2024

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