NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 29, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001048311.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr)]

NM_000527.5(LDLR):c.1879G>A (p.Ala627Thr)

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.1879G>A (p.Ala627Thr)

HGVS:

NC_000019.10:g.11120125G>A
NG_009060.1:g.35745G>A
NM_000527.5:c.1879G>AMANE SELECT
NM_001195798.2:c.1879G>A
NM_001195799.2:c.1756G>A
NM_001195800.2:c.1375G>A
NM_001195803.2:c.1498G>A
NP_000518.1:p.Ala627Thr
NP_000518.1:p.Ala627Thr
NP_001182727.1:p.Ala627Thr
NP_001182728.1:p.Ala586Thr
NP_001182729.1:p.Ala459Thr
NP_001182732.1:p.Ala500Thr
LRG_274t1:c.1879G>A
LRG_274:g.35745G>A
NC_000019.9:g.11230801G>A
NM_000527.4(LDLR):c.1879G>A
NM_000527.4:c.1879G>A
c.1879G>A

Protein change:

A459T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000259; dbSNP: rs879255066

NCBI 1000 Genomes Browser:

rs879255066

Molecular consequence:

NM_000527.5:c.1879G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1879G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1756G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1375G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1498G>A - 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

Rattus norvegicus CH230-261A11 (Children's Hospital Oakland Research Institute R...
Rattus norvegicus CH230-261A11 (Children's Hospital Oakland Research Institute Rat (BN/SsNHsd/MCW) BAC library) complete sequence
gi|224458426|gnl|bcmhgsc|project_gu ylor|gb|AC131864.3|

Nucleotide
LOC114827894 [Mus musculus]
LOC114827894 [Mus musculus]
Gene ID:114827894

Gene

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
SCV001212307	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 21376320, 23158915, 23375686, 25807990, 27206935, 27830735, 28235710, 28502510, 30108616, 7903864, 9763532, 28492532
SCV001355020	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 18, 2023)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 7903864, 19020990, 20538126, 23375686, 25807990, 27206935, 27830735, 28235710, 28502510, 30270083, 30400955, 34037665, 36226792, 36325061, 37397863, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001212307

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV001355020

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 18, 2023)

germline

clinical testing

PubMed (16)
[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

Array-based resequencing for mutations causing familial hypercholesterolemia.

Chiou KR, Charng MJ, Chang HM.

Atherosclerosis. 2011 Jun;216(2):383-9. doi: 10.1016/j.atherosclerosis.2011.02.006. Epub 2011 Mar 3.

PubMed [citation]

PMID:: 21376320

[The phenotypes of a hypercholesterolemia family with low density lipoprotein receptor exon 13 A606T mutation].

Cheng XY, Cheng XH, Zhang Y, Zheng F, Wang AL.

Zhonghua Nei Ke Za Zhi. 2012 Sep;51(9):680-2. Chinese.

PubMed [citation]

PMID:: 23158915

See all PubMed Citations (21)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001212307.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 627 of the LDLR protein (p.Ala627Thr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 7903864, 9763532, 21376320, 23158915, 23375686, 25807990, 27206935, 27830735, 28235710, 28502510, 30108616). This variant is also known as p.Ala606Thr. ClinVar contains an entry for this variant (Variation ID: 252101). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects LDLR function (PMID: 7903864). This variant disrupts the p.Ala627 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 9763532), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001355020.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (16)

Description

This missense variant (also known as p.Ala606Thr in the mature protein) replaces alanine with threonine at codon 627 in the LDLR type B repeat 6 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This LDLR variant has been reported in over 20 heterozygous individuals affected with familial hypercholesterolemia (PMID: 20538126, 23375686, 27206935, 27830735, 28235710, 30270083, 30400955, 34037665, 36226792, 37397863). This variant has also been observed in compound heterozygous state with a known pathogenic LDLR variant in several individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious LDLR variants (PMID: 7903864, 19020990, 25807990, 28502510, 36325061). This variant has been identified in 1/251494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, p.Ala627Val and p.Ala627Asp, are considered to be disease-causing (ClinVar variation ID: 252102 and 226377), suggesting that alanine at this position is important for LDLR protein function. Based on the available evidence, this variant is classified as Pathogenic.

#	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: Nov 3, 2024

ClinVar

Relating variation to medicine