NM_000527.5(LDLR):c.1448G>A (p.Trp483Ter) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 6, 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:: RCV001049393.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1448G>A (p.Trp483Ter)]

NM_000527.5(LDLR):c.1448G>A (p.Trp483Ter)

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.1448G>A (p.Trp483Ter)

HGVS:

NC_000019.10:g.11113624G>A
NG_009060.1:g.29244G>A
NM_000527.5:c.1448G>AMANE SELECT
NM_001195798.2:c.1448G>A
NM_001195799.2:c.1325G>A
NM_001195800.2:c.944G>A
NM_001195803.2:c.1067G>A
NP_000518.1:p.Trp483Ter
NP_000518.1:p.Trp483Ter
NP_001182727.1:p.Trp483Ter
NP_001182728.1:p.Trp442Ter
NP_001182729.1:p.Trp315Ter
NP_001182732.1:p.Trp356Ter
LRG_274t1:c.1448G>A
LRG_274:g.29244G>A
LRG_274p1:p.Trp483Ter
NC_000019.9:g.11224300G>A
NM_000527.4:c.1448G>A
c.1448G>A

Protein change:

W315*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001431; dbSNP: rs875989921

NCBI 1000 Genomes Browser:

rs875989921

Molecular consequence:

NM_000527.5:c.1448G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.1448G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1325G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.944G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.1067G>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
SCV001213439	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Apr 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 7903864, 18247305, 20809525, 28645073, 28492532
SCV001341142	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 4, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001213439

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Apr 6, 2023)

germline

clinical testing

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

SCV001341142

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 4, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Familial hypercholesterolemia in China. Identification of mutations in the LDL-receptor gene that result in a receptor-negative phenotype.

Sun XM, Patel DD, Webb JC, Knight BL, Fan LM, Cai HJ, Soutar AK.

Arterioscler Thromb. 1994 Jan;14(1):85-94.

PubMed [citation]

PMID:: 7903864

[Mutation screening and functional analysis of low density lipoprotein receptor in a familial hypercholesterolemia family].

Cheng XH, Zheng F, Zhou X, Xiong CL, Ding J, Chen YM.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2008 Feb;25(1):55-8. Chinese.

PubMed [citation]

PMID:: 18247305

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213439.5

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 226356). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7903864, 18247305). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp483*) 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

From Color Diagnostics, LLC DBA Color Health, SCV001341142.2

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

Description

This variant changes 1 nucleotide in exon 10 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 over 25 individuals affected with familial hypercholesterolemia (PMID: 23375686, 25846081, 27170061, 28235710, 28502495, 29233637). 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. Based on 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

Last Updated: Oct 26, 2024

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