NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Nov 7, 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:: RCV000505204.4

Allele description [Variation Report for NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe)]

NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe)

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.1739C>T (p.Ser580Phe)

Other names:

NM_000527.5(LDLR):c.1739C>T; p.Ser580Phe

HGVS:

NC_000019.10:g.11116892C>T
NG_009060.1:g.32512C>T
NM_000527.5:c.1739C>TMANE SELECT
NM_001195798.2:c.1739C>T
NM_001195799.2:c.1616C>T
NM_001195800.2:c.1235C>T
NM_001195803.2:c.1358C>T
NP_000518.1:p.Ser580Phe
NP_000518.1:p.Ser580Phe
NP_001182727.1:p.Ser580Phe
NP_001182728.1:p.Ser539Phe
NP_001182729.1:p.Ser412Phe
NP_001182732.1:p.Ser453Phe
LRG_274t1:c.1739C>T
LRG_274:g.32512C>T
LRG_274p1:p.Ser580Phe
NC_000019.9:g.11227568C>T
NM_000527.4:c.1739C>T
p.(Ser580Phe)

Protein change:

S412F

Links:

dbSNP: rs934496989

NCBI 1000 Genomes Browser:

rs934496989

Molecular consequence:

NM_000527.5:c.1739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1739C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1616C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1235C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1358C>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

Recent activity

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Homo sapiens sulfotransferase family, cytosolic, 1C, member 4, mRNA (cDNA clone ...
Homo sapiens sulfotransferase family, cytosolic, 1C, member 4, mRNA (cDNA clone MGC:149521 IMAGE:40115974), complete cds
gi|115527985|gb|BC125043.1|

Nucleotide
RecName: Full=Olfactory receptor 8H2; AltName: Full=Olfactory receptor OR11-171
RecName: Full=Olfactory receptor 8H2; AltName: Full=Olfactory receptor OR11-171
gi|38372643|sp|Q8N162.1|OR8H2_HUMAN

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000599390	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
SCV001653651	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 (3) [See all records that cite these PMIDs] 21865347, 32977124, 25741868
SCV005328523	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely Pathogenic (Nov 7, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000599390

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]

SCV001653651

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 (3)
[See all records that cite these PMIDs]

SCV005328523

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Likely Pathogenic
(Nov 7, 2023)

germline

curation

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

Citation Link

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	curation
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	germline	yes	8	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

Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features.

Bertolini S, Calandra S, Arca M, Averna M, Catapano AL, Tarugi P; Italian Study Group of Homozygous Familial Hypercholesterolemia..

Atherosclerosis. 2020 Nov;312:72-78. doi: 10.1016/j.atherosclerosis.2020.08.027. Epub 2020 Sep 9.

PubMed [citation]

PMID:: 32977124

See all PubMed Citations (4)

Details of each submission

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000599390.1

#	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, SCV001653651.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	8	not provided	not provided	clinical testing	PubMed (3)

#	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		8	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005328523.1

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

Description

The NM_000527.5(LDLR):c.1739C>T (p.Ser580Phe) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, PP1, PP3, PP4, PS3_Supporting and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 7 November 2023. The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 (0.001%) in European (Non-Finnish) exomes+genomes (gnomAD v2.1.1). PP3: REVEL=0.907. PS3_Supporting: Level 3 assay: PMID 35474963 (Pfisterer SG et al., 2022): Heterozygous patient monocytes and lymphocytes. 25-50% of control low-density lipoprotein particle uptake and LDLR surface expression. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (1 case from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France; 2 cases from Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca). PP1: Variant segregates with FH phenotype in 2 informative meioses identified by Research Lab of Molecular Genetics of Lipid Metabolism, Italy - Prof. M. Arca. 1 affected family member has the variant and 1 unaffected family member does not have the variant.

#	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: Oct 8, 2024

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