NM_000527.5(LDLR):c.2307C>G (p.His769Gln) AND Familial hypercholesterolemia

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Jul 19, 2024
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:: RCV001182969.11

Allele description [Variation Report for NM_000527.5(LDLR):c.2307C>G (p.His769Gln)]

NM_000527.5(LDLR):c.2307C>G (p.His769Gln)

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.2307C>G (p.His769Gln)

HGVS:

NC_000019.10:g.11123340C>G
NG_009060.1:g.38960C>G
NM_000527.5:c.2307C>GMANE SELECT
NM_001195798.2:c.2307C>G
NM_001195799.2:c.2184C>G
NM_001195800.2:c.1803C>G
NM_001195803.2:c.1773C>G
NP_000518.1:p.His769Gln
NP_001182727.1:p.His769Gln
NP_001182728.1:p.His728Gln
NP_001182729.1:p.His601Gln
NP_001182732.1:p.His591Gln
LRG_274t1:c.2307C>G
LRG_274:g.38960C>G
NC_000019.9:g.11234016C>G
NC_000019.9:g.11234016C>G
NM_000527.4:c.2307C>G

Protein change:

H591Q

Links:

dbSNP: rs760479588

NCBI 1000 Genomes Browser:

rs760479588

Molecular consequence:

NM_000527.5:c.2307C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2307C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2184C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1803C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1773C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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
SCV001348606	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 6, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002946374	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jul 19, 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

SCV001348606

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 6, 2024)

germline

clinical testing

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

SCV002946374

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely benign
(Jul 19, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001348606.5

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

Description

This missense variant (also known as p.His748Gln in the mature protein) replaces histidine with glutamine at codon 769 of the LDLR protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 11/250704 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002946374.3

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

Last Updated: May 16, 2025

ClinVar

Relating variation to medicine