NM_000527.5(LDLR):c.1257C>G (p.Tyr419Ter) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 17, 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:: RCV001216540.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1257C>G (p.Tyr419Ter)]

NM_000527.5(LDLR):c.1257C>G (p.Tyr419Ter)

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.1257C>G (p.Tyr419Ter)

HGVS:

NC_000019.10:g.11113348C>G
NG_009060.1:g.28968C>G
NM_000527.5:c.1257C>GMANE SELECT
NM_001195798.2:c.1257C>G
NM_001195799.2:c.1134C>G
NM_001195800.2:c.753C>G
NM_001195803.2:c.876C>G
NP_000518.1:p.Tyr419Ter
NP_000518.1:p.Tyr419Ter
NP_001182727.1:p.Tyr419Ter
NP_001182728.1:p.Tyr378Ter
NP_001182729.1:p.Tyr251Ter
NP_001182732.1:p.Tyr292Ter
LRG_274t1:c.1257C>G
LRG_274:g.28968C>G
LRG_274p1:p.Tyr419Ter
NC_000019.9:g.11224024C>G
NM_000527.4:c.1257C>G
c.1257C>G
p.Tyr419*

Protein change:

Y251*

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000539; dbSNP: rs774439908

NCBI 1000 Genomes Browser:

rs774439908

Molecular consequence:

NM_000527.5:c.1257C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195798.2:c.1257C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195799.2:c.1134C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195800.2:c.753C>G - nonsense - [Sequence Ontology: SO:0001587]
NM_001195803.2:c.876C>G - 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
SCV001388343	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 20809525, 28645073, 16183066, 28965616, 28492532
SCV001737685	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 14, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16183066, 28965616, 32977124 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001388343

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2023)

germline

clinical testing

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

SCV001737685

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jun 14, 2021)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

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 spectrum of autosomal dominant hypercholesterolemia in France.

Marduel M, Carrié A, Sassolas A, Devillers M, Carreau V, Di Filippo M, Erlich D, Abifadel M, Marques-Pinheiro A, Munnich A, Junien C; French ADH Research Network., Boileau C, Varret M, Rabès JP.

Hum Mutat. 2010 Nov;31(11):E1811-24. doi: 10.1002/humu.21348.

PubMed [citation]

PMID:: 20809525
PMCID:: PMC3152176

Analysis of LDLR variants from homozygous FH patients carrying multiple mutations in the LDLR gene.

Jiang L, Benito-Vicente A, Tang L, Etxebarria A, Cui W, Uribe KB, Pan XD, Ostolaza H, Yang SW, Zhou YJ, Martin C, Wang LY.

Atherosclerosis. 2017 Aug;263:163-170. doi: 10.1016/j.atherosclerosis.2017.06.014. Epub 2017 Jun 8.

PubMed [citation]

PMID:: 28645073

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001388343.5

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

Description

This sequence change creates a premature translational stop signal (p.Tyr419*) 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). This variant is present in population databases (rs774439908, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 16183066, 28965616). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 251758). For these reasons, this variant has been 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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001737685.1

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

Description

Variant summary: LDLR c.1257C>G (p.Tyr419X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251248 control chromosomes. c.1257C>G has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia and subsequently included in other studies reporting overlapping cohorts (example, Pisciotta_2006, Pirillo_2017, Bertollini_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 13, 2024

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