NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn) AND Hypercholesterolemia, familial, 1

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Apr 27, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000237445.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn)]

NM_000527.5(LDLR):c.1088C>A (p.Thr363Asn)

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.1088C>A (p.Thr363Asn)

HGVS:

NC_000019.10:g.11111541C>A
NG_009060.1:g.27161C>A
NM_000527.5:c.1088C>AMANE SELECT
NM_001195798.2:c.1088C>A
NM_001195799.2:c.965C>A
NM_001195800.2:c.584C>A
NM_001195803.2:c.707C>A
NP_000518.1:p.Thr363Asn
NP_000518.1:p.Thr363Asn
NP_001182727.1:p.Thr363Asn
NP_001182728.1:p.Thr322Asn
NP_001182729.1:p.Thr195Asn
NP_001182732.1:p.Thr236Asn
LRG_274t1:c.1088C>A
LRG_274:g.27161C>A
LRG_274p1:p.Thr363Asn
NC_000019.9:g.11222217C>A
NM_000527.4:c.1088C>A
c.1088C>A

Protein change:

T195N

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001354; dbSNP: rs200533979

NCBI 1000 Genomes Browser:

rs200533979

Molecular consequence:

NM_000527.5:c.1088C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1088C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.965C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.584C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.707C>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypercholesterolemia, familial, 1
Synonyms:: LDL RECEPTOR DISORDER; Hyperlipoproteinemia Type IIa; HYPER-LOW-DENSITY-LIPOPROTEINEMIA; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007750; MedGen: C0745103; Orphanet: 391665; OMIM: 143890

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Stt3B [Acyrthosiphon pisum]
Stt3B [Acyrthosiphon pisum]
Gene ID:100163072

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295211	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000322932	Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 1, 2016)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001653489	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004827019	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Apr 27, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	1	not provided	research, literature only
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Mutational analysis of a cohort with clinical diagnosis of familial hypercholesterolemia: considerations for genetic diagnosis improvement.

Medeiros AM, Alves AC, Bourbon M.

Genet Med. 2016 Apr;18(4):316-24. doi: 10.1038/gim.2015.71. Epub 2015 May 28.

PubMed [citation]

PMID:: 26020417

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

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295211.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	literature only	PubMed (1)

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

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322932.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)
2	not provided	not provided	not provided	not provided	research	PubMed (1)

Description

0/208 non-FH alleles

#	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
2	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001653489.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004827019.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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