NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Nov 1, 2022
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:: RCV001213617.3

Allele description [Variation Report for NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys)]

NM_000527.5(LDLR):c.1394A>G (p.Tyr465Cys)

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.1394A>G (p.Tyr465Cys)

HGVS:

NC_000019.10:g.11113570A>G
NG_009060.1:g.29190A>G
NM_000527.5:c.1394A>GMANE SELECT
NM_001195798.2:c.1394A>G
NM_001195799.2:c.1271A>G
NM_001195800.2:c.890A>G
NM_001195803.2:c.1013A>G
NP_000518.1:p.Tyr465Cys
NP_000518.1:p.Tyr465Cys
NP_001182727.1:p.Tyr465Cys
NP_001182728.1:p.Tyr424Cys
NP_001182729.1:p.Tyr297Cys
NP_001182732.1:p.Tyr338Cys
LRG_274t1:c.1394A>G
LRG_274:g.29190A>G
LRG_274p1:p.Tyr465Cys
NC_000019.9:g.11224246A>G
NM_000527.4:c.1394A>G
c.1394A>G

Protein change:

Y297C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001421; dbSNP: rs879254889

NCBI 1000 Genomes Browser:

rs879254889

Molecular consequence:

NM_000527.5:c.1394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1394A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1271A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.890A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1013A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

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maltase-glucoamylase, intestinal isoform X3 [Delphinapterus leucas]
maltase-glucoamylase, intestinal isoform X3 [Delphinapterus leucas]
gi|1246147653|ref|XP_022435021.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001385254	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22698793, 33740630, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001385254

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 1, 2022)

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

The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations.

Tichý L, Freiberger T, Zapletalová P, Soška V, Ravčuková B, Fajkusová L.

Atherosclerosis. 2012 Aug;223(2):401-8. doi: 10.1016/j.atherosclerosis.2012.05.014. Epub 2012 May 23.

PubMed [citation]

PMID:: 22698793

Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020.

Leren TP, Bogsrud MP.

Atherosclerosis. 2021 Apr;322:61-66. doi: 10.1016/j.atherosclerosis.2021.02.022. Epub 2021 Feb 23.

PubMed [citation]

PMID:: 33740630

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001385254.2

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

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 465 of the LDLR protein (p.Tyr465Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 22698793, 33740630). ClinVar contains an entry for this variant (Variation ID: 251826). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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