NM_000527.5(LDLR):c.313+6T>C AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Aug 26, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000238504.4

Allele description [Variation Report for NM_000527.5(LDLR):c.313+6T>C]

NM_000527.5(LDLR):c.313+6T>C

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.313+6T>C

HGVS:

NC_000019.10:g.11102792T>C
NG_009060.1:g.18412T>C
NM_000527.5:c.313+6T>CMANE SELECT
NM_001195798.2:c.313+6T>C
NM_001195799.2:c.191-2428T>C
NM_001195800.2:c.313+6T>C
NM_001195803.2:c.313+6T>C
LRG_274t1:c.313+6T>C
LRG_274:g.18412T>C
NC_000019.9:g.11213468T>C
NM_000527.4:c.313+6T>C
c.313+6T>C

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000047; dbSNP: rs879254468

NCBI 1000 Genomes Browser:

rs879254468

Molecular consequence:

NM_000527.5:c.313+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195798.2:c.313+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195799.2:c.191-2428T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195800.2:c.313+6T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.313+6T>C - intron variant - [Sequence Ontology: SO:0001627]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000294612	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,
SCV000322891	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 (2) [See all records that cite these PMIDs] 25741868, 19411563
SCV002817163	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Aug 26, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000294612

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,

SCV000322891

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 (2)
[See all records that cite these PMIDs]

SCV002817163

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Aug 26, 2022)

germline

curation

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	curation
not provided	germline	yes	1	not provided	not provided	1	not provided	research, literature only

Citations

PubMed

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

Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations.

Bourbon M, Duarte MA, Alves AC, Medeiros AM, Marques L, Soutar AK.

J Med Genet. 2009 May;46(5):352-7. doi: 10.1136/jmg.2007.057000.

PubMed [citation]

PMID:: 19411563

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000294612.2

#	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, SCV000322891.1

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

Description

"Heterozygous patients' lymphocytes, RNA assays"

PubMed [ID: 19411563]

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 ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002817163.1

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

Description

The NM_000527.5 (LDLR):c.313+6T>C variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP4, PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: This variant is absent from gnomAD (gnomAD v2.1.1). PP4: Variant meets PM2 and is identified in 1 index case who fulfils Simon Brome criteria for possible FH after alternative causes of high cholesterol were excluded, reported by Bourbon et al from Unidade de Investigação Cardiovascular, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal (PMID 19411563). PS3_Supporting: Level 3 experiment, heterozygous patients’ lymphocytes were used for RNA assay and exon 3 skipping (p.Leu64_Pro105delinsSer) was observed, reported by Bourbon et al (PMID 19411563). PM3 not met: This variant is identified in an index case with one other variant, LDLR c.1291G>A (p.Ala431Thr), classified as Pathogenic by these guidelines, in trans, reported by Bourbon et al (PMID 19411563).However, patient’s untreated LDL-C is 435mg/dl, which is under 500mg/dl, therefore PM3 is not met. PP1 not met: Variant segregates with FH phenotype in 1 (less than 2) informative meiosis from 1 family who was tested positive for the variant with LDL-C > 75th percentile, reported by Bourbon et al (PMID 19411563).

#	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: Jun 23, 2024

ClinVar

Relating variation to medicine