NM_000527.5(LDLR):c.1383C>T (p.Gly461=) AND Hypercholesterolemia, familial, 1

Germline classification:: Likely benign (4 submissions)
Last evaluated:: Jul 2, 2024
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:: RCV000237794.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1383C>T (p.Gly461=)]

NM_000527.5(LDLR):c.1383C>T (p.Gly461=)

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.1383C>T (p.Gly461=)

Other names:

NM_000527.5(LDLR):c.1383C>T; p.Gly461=

HGVS:

NC_000019.10:g.11113559C>T
NG_009060.1:g.29179C>T
NM_000527.5:c.1383C>TMANE SELECT
NM_001195798.2:c.1383C>T
NM_001195799.2:c.1260C>T
NM_001195800.2:c.879C>T
NM_001195803.2:c.1002C>T
NP_000518.1:p.Gly461=
NP_000518.1:p.Gly461=
NP_001182727.1:p.Gly461=
NP_001182728.1:p.Gly420=
NP_001182729.1:p.Gly293=
NP_001182732.1:p.Gly334=
LRG_274t1:c.1383C>T
LRG_274:g.29179C>T
LRG_274p1:p.Gly461=
NC_000019.9:g.11224235C>T
NM_000527.4:c.1383C>T
c.1383C>T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001419; dbSNP: rs764929176

NCBI 1000 Genomes Browser:

rs764929176

Molecular consequence:

NM_000527.5:c.1383C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1383C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1260C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.879C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.1002C>T - synonymous variant - [Sequence Ontology: SO:0001819]

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000295407	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely benign (Mar 25, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000322948	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]
SCV004820308	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Dec 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005328518	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Likely Benign (Jul 2, 2024)	germline	curation	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	10	not provided	not provided	108545	not provided	clinical testing, literature only, curation
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research

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, SCV000295407.2

#	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	unknown	1	not provided	not provided		1	not provided	not provided	not provided

From Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, SCV000322948.1

#	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

%MAF (ExAC):0.001655

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 All of Us Research Program, National Institutes of Health, SCV004820308.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	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		9	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV005328518.1

#	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.1383C>T (p.Gly461=) variant is classified as Likely Benign for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PM2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 2 July 2024. The supporting evidence is as follows: PM2: PopMax MAF = 0.0001157 (0.01157%) in the Latino-admixed population exomes (gnomAD v2.1.1). BP4: No REVEL, splicing evaluation required: A) not on limits B) does not create GT. Variant is not predicted to alter splicing. BP7: Variant is synonymous and meets BP4. This variant has two supporting strength evidence codes towards Benign, enough to classify as Likely Benign, and only one moderate strength evidence code towards Pathogenic. VCEP consensus is that PM2 is not strong enough evidence to upgrade the classification of an otherwise Benign or Likely Benign variant.

#	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 8, 2024

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