NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 22, 2021
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:: RCV004017548.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr)]

NM_000527.5(LDLR):c.1019G>A (p.Cys340Tyr)

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.1019G>A (p.Cys340Tyr)

HGVS:

NC_000019.10:g.11110730G>A
NG_009060.1:g.26350G>A
NM_000527.5:c.1019G>AMANE SELECT
NM_001195798.2:c.1019G>A
NM_001195799.2:c.896G>A
NM_001195800.2:c.515G>A
NM_001195803.2:c.638G>A
NP_000518.1:p.Cys340Tyr
NP_000518.1:p.Cys340Tyr
NP_001182727.1:p.Cys340Tyr
NP_001182728.1:p.Cys299Tyr
NP_001182729.1:p.Cys172Tyr
NP_001182732.1:p.Cys213Tyr
LRG_274t1:c.1019G>A
LRG_274:g.26350G>A
LRG_274p1:p.Cys340Tyr
NC_000019.9:g.11221406G>A
NM_000527.4:c.1019G>A
c.1019G>A

Protein change:

C172Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000837; dbSNP: rs755757866

NCBI 1000 Genomes Browser:

rs755757866

Molecular consequence:

NM_000527.5:c.1019G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1019G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.896G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.515G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.638G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848201	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Feb 22, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 15241806, 27824480, 30592178, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848201

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(Feb 22, 2021)

germline

clinical testing

PubMed (4)
[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

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mozas P, Castillo S, Tejedor D, Reyes G, Alonso R, Franco M, Saenz P, Fuentes F, Almagro F, Mata P, Pocoví M.

Hum Mutat. 2004 Aug;24(2):187.

PubMed [citation]

PMID:: 15241806

The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey.

Gabčová D, Vohnout B, Staníková D, Hučková M, Kadurová M, Debreová M, Kozárová M, Fábryová Ľ, Staník J, Klimeš I, Rašlová K, Gašperiková D.

Physiol Res. 2017 Mar 31;66(1):75-84. Epub 2016 Nov 8.

PubMed [citation]

PMID:: 27824480

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848201.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Cys340Tyr variant in LDLR has been reported in 5 individuals with hypercholesterolemia and segregated with disease in 3 affected relatives (Mozas 2014, Gabcova 2017, Chan 2019). It was absent from large population studies. This variant has been reported in ClinVar (Variation ID: 251600). Three additional variants at this codon have been reported in individuals with hypercholesterolemia (p.Cys340Phe, p.Cys340Trp, and p.Cys340Leu), suggesting that changes at this position may not be tolerated. Computational prediction tools and conservation analysis suggest that the p.Cys340Tyr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant familial hypercholesterolemia. ACMG/AMP Criteria applied: PM2, PP1, PP3, PS4_Supporting, PM5_Supporting.

#	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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