NM_000527.5(LDLR):c.1200C>A (p.Tyr400Ter) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000775059.10

Allele description [Variation Report for NM_000527.5(LDLR):c.1200C>A (p.Tyr400Ter)]

NM_000527.5(LDLR):c.1200C>A (p.Tyr400Ter)

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.1200C>A (p.Tyr400Ter)

HGVS:

NC_000019.10:g.11113291C>A
NG_009060.1:g.28911C>A
NM_000527.5:c.1200C>AMANE SELECT
NM_001195798.2:c.1200C>A
NM_001195799.2:c.1077C>A
NM_001195800.2:c.696C>A
NM_001195803.2:c.819C>A
NP_000518.1:p.Tyr400Ter
NP_000518.1:p.Tyr400Ter
NP_001182727.1:p.Tyr400Ter
NP_001182728.1:p.Tyr359Ter
NP_001182729.1:p.Tyr232Ter
NP_001182732.1:p.Tyr273Ter
LRG_274t1:c.1200C>A
LRG_274:g.28911C>A
LRG_274p1:p.Tyr400Ter
NC_000019.9:g.11223967C>A
NM_000527.4:c.1200C>A
c.1200C>A

Protein change:

Y232*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000840; dbSNP: rs879254827

NCBI 1000 Genomes Browser:

rs879254827

Molecular consequence:

NM_000527.5:c.1200C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.1200C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1077C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.696C>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.819C>A - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000909160	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 16, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15241806, 16250003, 18096825, 34037665, 25741868
SCV000941734	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 18, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15241806, 16250003, 18096825, 20809525, 28645073, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909160

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 16, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000941734

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 18, 2023)

germline

clinical testing

PubMed (6)
[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

Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis.

Sturm AC, Truty R, Callis TE, Aguilar S, Esplin ED, Garcia S, Haverfield EV, Morales A, Nussbaum RL, Rojahn S, Vatta M, Rader DJ.

JAMA Cardiol. 2021 Aug 1;6(8):902-909. doi: 10.1001/jamacardio.2021.1301.

PubMed [citation]

PMID:: 34037665
PMCID:: PMC8156154

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000909160.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant changes 1 nucleotide in exon 9 of the EGF precursor homology domain of the LDLR gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825). It has also been reported in an individual suspected to be affected with familial hypercholesterolemia (PMID: 34037665). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of LDLR function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000941734.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 251728). This variant is also known as p.Y379X. This premature translational stop signal has been observed in individuals with familial hypercholesterolemia (PMID: 15241806, 16250003, 18096825; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr400*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073).

#	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: Feb 25, 2025

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