NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Mar 3, 2019
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:: RCV000826175.6

Allele description [Variation Report for NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)]

NM_000527.5(LDLR):c.938G>A (p.Cys313Tyr)

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.938G>A (p.Cys313Tyr)

HGVS:

NC_000019.10:g.11107512G>A
NG_009060.1:g.23132G>A
NM_000527.5:c.938G>AMANE SELECT
NM_001195798.2:c.938G>A
NM_001195799.2:c.815G>A
NM_001195800.2:c.434G>A
NM_001195803.2:c.557G>A
NP_000518.1:p.Cys313Tyr
NP_000518.1:p.Cys313Tyr
NP_001182727.1:p.Cys313Tyr
NP_001182728.1:p.Cys272Tyr
NP_001182729.1:p.Cys145Tyr
NP_001182732.1:p.Cys186Tyr
LRG_274t1:c.938G>A
LRG_274:g.23132G>A
LRG_274p1:p.Cys313Tyr
NC_000019.9:g.11218188G>A
NM_000527.4:c.938G>A
P01130:p.Cys313Tyr
c.938G>A

Protein change:

C145Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001871; UniProtKB: P01130#VAR_005358; dbSNP: rs875989911

NCBI 1000 Genomes Browser:

rs875989911

Molecular consequence:

NM_000527.5:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.938G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.815G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.434G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000967714	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Mar 3, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11040093, 28349240, 21382890, 11857755, 9259195, 27680772, 11810272, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967714

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Mar 3, 2019)

germline

clinical testing

PubMed (8)
[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	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutation analysis in a small cohort of New Zealand patients originating from the United Kingdom demonstrates genetic heterogeneity in familial hypercholesterolemia.

Thiart R, Varret M, Lintott CJ, Scott RS, Loubser O, du Plessis L, de Villiers JN, Boileau C, Kotze MJ.

Mol Cell Probes. 2000 Oct;14(5):299-304.

PubMed [citation]

PMID:: 11040093

The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.

Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN.

Hum Genet. 2017 Jun;136(6):665-677. doi: 10.1007/s00439-017-1779-6. Epub 2017 Mar 27. Review.

PubMed [citation]

PMID:: 28349240
PMCID:: PMC5429360

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967714.2

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

Description

The p.Cys313Tyr variant in LDLR (also described as p.Cys292Tyr in the literature) has been reported in >10 individuals with familial hypercholesterolemia (FH), of which 2 are in the compound heterozygous state (Day 1997, Thiart 2000, Fouchier 2001, Bunn 2002, Van der Graaf 2011, Martin 2016). It has also been reported in ClinVar (Variation ID: 226339) and was absent from large population studies. Computational prediction tools and conservation analysis suggest that the p.Cys131Tyr variant may impact the protein. This variant is located in the last three bases of the exon, which is part of the 5â€™ splice region. Computational tools do not suggest an impact to splicing. Additionally, other missense variants at this amino acid position (p.Cys313Arg, p.Cys313Gly and p.Cys313Trp) have been reported in individuals with familial hypercholesterolemia (Human Gene Mutation Database: Stenson 2017), suggesting that changes at this position may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Cys313Tyr variant is likely pathogenic. The ACMG/AMP Criteria applied (Richards 2015): PS4_Moderate, PM2, PP3, 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		1	not provided	1	not provided

Last Updated: Sep 29, 2024

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