NM_000527.5(LDLR):c.2301G>A (p.Met767Ile) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Dec 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000775614.5

Allele description [Variation Report for NM_000527.5(LDLR):c.2301G>A (p.Met767Ile)]

NM_000527.5(LDLR):c.2301G>A (p.Met767Ile)

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.2301G>A (p.Met767Ile)

HGVS:

NC_000019.10:g.11123334G>A
NG_009060.1:g.38954G>A
NM_000527.5:c.2301G>AMANE SELECT
NM_001195798.2:c.2301G>A
NM_001195799.2:c.2178G>A
NM_001195800.2:c.1797G>A
NM_001195803.2:c.1767G>A
NP_000518.1:p.Met767Ile
NP_000518.1:p.Met767Ile
NP_001182727.1:p.Met767Ile
NP_001182728.1:p.Met726Ile
NP_001182729.1:p.Met599Ile
NP_001182732.1:p.Met589Ile
LRG_274t1:c.2301G>A
LRG_274:g.38954G>A
LRG_274p1:p.Met767Ile
NC_000019.9:g.11234010G>A
NM_000527.4:c.2301G>A

Protein change:

M589I

Links:

dbSNP: rs149237737

NCBI 1000 Genomes Browser:

rs149237737

Molecular consequence:

NM_000527.5:c.2301G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2301G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1797G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1767G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000909978	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Dec 5, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 34615865, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000909978

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Dec 5, 2023)

germline

clinical testing

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

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	clinical testing

Citations

PubMed

Calibrated rare variant genetic risk scores for complex disease prediction using large exome sequence repositories.

Lali R, Chong M, Omidi A, Mohammadi-Shemirani P, Le A, Cui E, Paré G.

Nat Commun. 2021 Oct 6;12(1):5852. doi: 10.1038/s41467-021-26114-0.

PubMed [citation]

PMID:: 34615865
PMCID:: PMC8494733

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 Color Diagnostics, LLC DBA Color Health, SCV000909978.4

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

Description

This missense variant replaces methionine with isoleucine at codon 767 of the LDLR protein. This variant is also known as p.Met746Ile in the mature protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with coronary artery disease (PMID: 34615865). This variant has been identified in 9/282280 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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: Sep 1, 2024

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