NM_000527.5(LDLR):c.1323C>T (p.Ile441=) AND Hypercholesterolemia, familial, 1

Germline classification:: Benign (3 submissions)
Last evaluated:: Jun 23, 2021
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:: RCV000548668.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1323C>T (p.Ile441=)]

NM_000527.5(LDLR):c.1323C>T (p.Ile441=)

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.1323C>T (p.Ile441=)

Other names:

NM_000527.4(LDLR):c.1323C>T; p.Ile441=

HGVS:

NC_000019.10:g.11113414C>T
NG_009060.1:g.29034C>T
NM_000527.5:c.1323C>TMANE SELECT
NM_001195798.2:c.1323C>T
NM_001195799.2:c.1200C>T
NM_001195800.2:c.819C>T
NM_001195803.2:c.942C>T
NP_000518.1:p.Ile441=
NP_000518.1:p.Ile441=
NP_001182727.1:p.Ile441=
NP_001182728.1:p.Ile400=
NP_001182729.1:p.Ile273=
NP_001182732.1:p.Ile314=
LRG_274t1:c.1323C>T
LRG_274:g.29034C>T
LRG_274p1:p.Ile441=
NC_000019.9:g.11224090C>T
NM_000527.4:c.1323C>T

Links:

dbSNP: rs5933

NCBI 1000 Genomes Browser:

rs5933

Molecular consequence:

NM_000527.5:c.1323C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.1323C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.1200C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.819C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.942C>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
SCV000782912	Robarts Research Institute, Western University	criteria provided, single submitter (ACMG Guidelines, 2015)	Benign (Jan 2, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001960952	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-1)	Benign (Jun 23, 2021)	germline	curation	Citation Link,
SCV004820297	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Benign (Feb 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000782912

Robarts Research Institute, Western University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Benign
(Jan 2, 2018)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001960952

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-1)

Benign
(Jun 23, 2021)

germline

curation

Citation Link,

SCV004820297

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Benign
(Feb 5, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	93	not provided	not provided	108544	not provided	clinical testing, curation

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

Details of each submission

From Robarts Research Institute, Western University, SCV000782912.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV001960952.1

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

Description

The NM_000527.4(LDLR):c.1323C>T (p.Ile441=) variant is classified as Benign for Familial Hypercholesterolemia by applying evidence codes BS1, BS2, BP4 and BP7 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: BS1 - FAF = 0.003722 (0.37%) in African exomes (gnomAD v2.1.1). BS2 - Variant is observed in heterozygosity in 5 normolipidemic adults. BP4 - no REVEL, splicing evaluation required. No functional study performed. A) not on limits B) does not create GT C) no GT nearby. BP7 - Variant is synonymous and meets BP4.

#	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 All of Us Research Program, National Institutes of Health, SCV004820297.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	93	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		93	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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