NM_000527.5(LDLR):c.1829C>T (p.Ser610Phe) AND Familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 22, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003581633.2

Allele description [Variation Report for NM_000527.5(LDLR):c.1829C>T (p.Ser610Phe)]

NM_000527.5(LDLR):c.1829C>T (p.Ser610Phe)

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.1829C>T (p.Ser610Phe)

HGVS:

NC_000019.10:g.11116982C>T
NG_009060.1:g.32602C>T
NM_000527.5:c.1829C>TMANE SELECT
NM_001195798.2:c.1829C>T
NM_001195799.2:c.1706C>T
NM_001195800.2:c.1325C>T
NM_001195803.2:c.1448C>T
NP_000518.1:p.Ser610Phe
NP_000518.1:p.Ser610Phe
NP_001182727.1:p.Ser610Phe
NP_001182728.1:p.Ser569Phe
NP_001182729.1:p.Ser442Phe
NP_001182732.1:p.Ser483Phe
LRG_274t1:c.1829C>T
LRG_274:g.32602C>T
LRG_274p1:p.Ser610Phe
NC_000019.9:g.11227658C>T
NM_000527.4:c.1829C>T
c.1829C>T

Protein change:

S442F

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001529; dbSNP: rs879255038

NCBI 1000 Genomes Browser:

rs879255038

Molecular consequence:

NM_000527.5:c.1829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1706C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1325C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1448C>T - 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
SCV004298373	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 22, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10532689, 31491741, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004298373

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 22, 2023)

germline

clinical testing

PubMed (3)
[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

Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia.

Jensen HK, Jensen LG, Meinertz H, Hansen PS, Gregersen N, Faergeman O.

Atherosclerosis. 1999 Oct;146(2):337-44.

PubMed [citation]

PMID:: 10532689

Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients.

Hori M, Ohta N, Takahashi A, Masuda H, Isoda R, Yamamoto S, Son C, Ogura M, Hosoda K, Miyamoto Y, Harada-Shiba M.

Atherosclerosis. 2019 Oct;289:101-108. doi: 10.1016/j.atherosclerosis.2019.08.004. Epub 2019 Aug 19.

PubMed [citation]

PMID:: 31491741

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004298373.1

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Ser610 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 252055). This variant is also known as S589F. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 10532689, 31491741). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 610 of the LDLR protein (p.Ser610Phe).

#	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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