NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu) AND Hypercholesterolemia, familial, 1

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 25, 2022
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:: RCV000237946.5

Allele description [Variation Report for NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu)]

NM_000527.5(LDLR):c.2100C>G (p.Asp700Glu)

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.2100C>G (p.Asp700Glu)

Other names:

NM_000527.5(LDLR):c.2100C>G

HGVS:

NC_000019.10:g.11120482C>G
NG_009060.1:g.36102C>G
NM_000527.5:c.2100C>GMANE SELECT
NM_001195798.2:c.2100C>G
NM_001195799.2:c.1977C>G
NM_001195800.2:c.1596C>G
NM_001195803.2:c.1606+249C>G
NP_000518.1:p.Asp700Glu
NP_001182727.1:p.Asp700Glu
NP_001182728.1:p.Asp659Glu
NP_001182729.1:p.Asp532Glu
LRG_274:g.36102C>G
NC_000019.9:g.11231158C>G
P01130:p.Asp700Glu
c.2100C>G

Protein change:

D532E

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000280; UniProtKB: P01130#VAR_005412; dbSNP: rs759858813

NCBI 1000 Genomes Browser:

rs759858813

Molecular consequence:

NM_001195803.2:c.1606+249C>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.2100C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2100C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1977C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1596C>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000295874	LDLR-LOVD, British Heart Foundation	criteria provided, single submitter (ACGS Guidelines, 2013)	Likely pathogenic (Mar 25, 2016)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 10206683, 21418584 Citation Link,
SCV002506378	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2)	Uncertain significance (Mar 25, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000295874

LDLR-LOVD, British Heart Foundation

criteria provided, single submitter

(ACGS Guidelines, 2013)

Likely pathogenic
(Mar 25, 2016)

germline

literature only

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

Citation Link,

SCV002506378

ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel

reviewed by expert panel

(ClinGen FH ACMG Specifications v1-2)

Uncertain significance
(Mar 25, 2022)

germline

curation

Citation Link

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	curation
not provided	germline	yes	2	not provided	not provided	2	not provided	literature only

Citations

PubMed

Identification of recurrent and novel mutations in the LDL receptor gene in Spanish patients with familial hypercholesterolemia. Mutations in brief no. 135. Online.

Cenarro A, Jensen HK, Casao E, Civeira F, González-Bonillo J, Rodríguez-Rey JC, Gregersen N, Pocoví M.

Hum Mutat. 1998;11(5):413.

PubMed [citation]

PMID:: 10206683

Analysis of sequence variations in low-density lipoprotein receptor gene among Malaysian patients with familial hypercholesterolemia.

Al-Khateeb A, Zahri MK, Mohamed MS, Sasongko TH, Ibrahim S, Yusof Z, Zilfalil BA.

BMC Med Genet. 2011 Mar 19;12:40. doi: 10.1186/1471-2350-12-40.

PubMed [citation]

PMID:: 21418584
PMCID:: PMC3071311

Details of each submission

From LDLR-LOVD, British Heart Foundation, SCV000295874.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel, SCV002506378.1

#	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.2100C>G (p.Asp700Glu) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes PM2, PS4_Supporting and PP4 as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - This variant is absent from gnomAD (gnomAD v2.1.1), so PM2 is Met. PS4_Supporting - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill SB criteria for FH from Malaysia (PMID: 21418584), so PS4_Supporting is Met. PP4 - Variant meets PM2 and is identified in 5 unrelated index cases who fulfill clinical criteria for FH from several labs (see PS4 for details), so PP4 is Met.

#	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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