NM_000527.5(LDLR):c.1747C>T (p.His583Tyr) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: May 1, 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:: RCV000182342.11

Allele description [Variation Report for NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)]

NM_000527.5(LDLR):c.1747C>T (p.His583Tyr)

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.1747C>T (p.His583Tyr)

Other names:

p.H583Y:CAC>TAC; NP_000518.1:p.H583Y

HGVS:

NC_000019.10:g.11116900C>T
NG_009060.1:g.32520C>T
NM_000527.5:c.1747C>TMANE SELECT
NM_001195798.2:c.1747C>T
NM_001195799.2:c.1624C>T
NM_001195800.2:c.1243C>T
NM_001195803.2:c.1366C>T
NP_000518.1:p.His583Tyr
NP_000518.1:p.His583Tyr
NP_001182727.1:p.His583Tyr
NP_001182728.1:p.His542Tyr
NP_001182729.1:p.His415Tyr
NP_001182732.1:p.His456Tyr
LRG_274t1:c.1747C>T
LRG_274:g.32520C>T
LRG_274p1:p.His583Tyr
NC_000019.9:g.11227576C>T
NM_000527.4:c.1747C>T
c.1747C>T

Protein change:

H415Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000234; dbSNP: rs730882109

NCBI 1000 Genomes Browser:

rs730882109

Molecular consequence:

NM_000527.5:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1747C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1624C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1366C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000234652	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 13, 2021)	germline	clinical testing	Citation Link,
SCV001470531	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (May 1, 2023)	unknown	clinical testing	PubMed (21) [See all records that cite these PMIDs] 32041611, 32719484, 32154576, 32331935, 32800790, 32759540, 34037665, 33569482, 33994402, 35741760, 29233637, 23155708, 30592178, 30586733, 30526649, 22353362, 27206935, 29353225, 15741231, 7903864, 26467025
SCV001924783	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001971024	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002503309	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 15, 2021)	germline	clinical testing	PubMed (14) [See all records that cite these PMIDs] 7903864, 30526649, 30592178, 32041611, 32719484, 31491741, 30586733, 29233637, 32800790, 32331935, 23155708, 21511053, 31447099, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Exploring the genetic pathogenicity of aortic dissection from 72 Han Chinese individuals using next-generation sequencing.

Pan M, Chen S, Wang H, Wu S, Ding Z, Wang Y, Li L, Li Z, Liu Q.

Clin Genet. 2020 May;97(5):704-711. doi: 10.1111/cge.13729. Epub 2020 Mar 16.

PubMed [citation]

PMID:: 32154576

Targeted Genetic Analysis in a Chinese Cohort of 208 Patients Related to Familial Hypercholesterolemia.

Wang H, Yang H, Liu Z, Cui K, Zhang Y, Zhang Y, Zhao K, Yin K, Li W, Zhou Z.

J Atheroscler Thromb. 2020 Dec 1;27(12):1288-1298. doi: 10.5551/jat.54593. Epub 2020 Aug 6.

PubMed [citation]

PMID:: 32759540
PMCID:: PMC7840166

See all PubMed Citations (25)

Details of each submission

From GeneDx, SCV000234652.14

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant causes receptor-ligand complex degradation, with cells expressing this variant producing only about 50% mature protein and showing reduced surface expression of receptors (Sun et al., 1994; Van Hoof et al., 2005; Zhao et al., 2011); Also known as H562Y; This variant is associated with the following publications: (PMID: 16205024, 30270083, 21376320, 31491741, 7903864, 20538126, 15741231, 22353362, 21511053, 28028493, 27206935, 23155708, 30526649, 30592178, 30586733, 15494314, 29233637, 25846081, 28235710, 31447099, 32800790, 33223521, 32759540, 32695144, 33418990, 33569482, 32041611, 32719484, 32154576, 32331935, 34037665, 33994402, 34526433, 34573395, 34176852)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470531.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (21)

Description

The frequency of this variant in the general population, 0.0012 (24/19952 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a common familial hypercholesterolemia (FH) variant within the Chinese and East Asian populations (PMIDs: 33994402 (2021), 32759540 (2020), 32331935 (2020), 32800790 (2020), 30592178 (2019), 27206935 (2016), 23155708 (2012), 22353362 (2012), 7903864 (1994)). Additionally, the variant has been reported in individuals with FH across multiple ethnicities (PMIDs: 35741760 (2022), 33569482 (2021), 34037665 (2021), 32041611 (2020), 30526649 (2018), 29233637 (2018)). A functional study found that the presence of this variant is damaging to proper LDLR function (PMID: 15741231 (2005)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001924783.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001971024.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From AiLife Diagnostics, AiLife Diagnostics, SCV002503309.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (14)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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