NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp) AND Familial hypercholesterolemia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 27, 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:: RCV000791447.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)]

NM_000527.5(LDLR):c.1118G>A (p.Gly373Asp)

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.1118G>A (p.Gly373Asp)

Other names:

FH Potenza-2

HGVS:

NC_000019.10:g.11111571G>A
NG_009060.1:g.27191G>A
NM_000527.5:c.1118G>AMANE SELECT
NM_001195798.2:c.1118G>A
NM_001195799.2:c.995G>A
NM_001195800.2:c.614G>A
NM_001195803.2:c.737G>A
NP_000518.1:p.Gly373Asp
NP_000518.1:p.Gly373Asp
NP_001182727.1:p.Gly373Asp
NP_001182728.1:p.Gly332Asp
NP_001182729.1:p.Gly205Asp
NP_001182732.1:p.Gly246Asp
LRG_274t1:c.1118G>A
LRG_274:g.27191G>A
LRG_274p1:p.Gly373Asp
NC_000019.9:g.11222247G>A
NM_000527.4:c.1118G>A
P01130:p.Gly373Asp
c.1118G>A
p.(Gly373Asp)

Protein change:

G205D

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000320; UniProtKB: P01130#VAR_072845

Molecular consequence:

NM_000527.5:c.1118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.995G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.614G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.737G>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
SCV000825010	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 8, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735, 16159606, 20145306, 28492532
SCV001460269	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV004813643	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 27, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 15241806, 11810272, 9974426, 10978268, 34297352 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825010

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 8, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV001460269

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 16, 2020)

germline

clinical testing

SCV004813643

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 27, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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	clinical testing

Citations

PubMed

Molecular basis of familial hypercholesterolemia in Brazil: Identification of seven novel LDLR gene mutations.

Salazar LA, Hirata MH, Cavalli SA, Nakandakare ER, Forti N, Diament J, Giannini SD, Bertolami MC, Hirata RD.

Hum Mutat. 2002 Apr;19(4):462-3.

PubMed [citation]

PMID:: 11933210

Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.

van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ, Wiegman A.

Circulation. 2011 Mar 22;123(11):1167-73. doi: 10.1161/CIRCULATIONAHA.110.979450. Epub 2011 Mar 7.

PubMed [citation]

PMID:: 21382890

See all PubMed Citations (12)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825010.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 373 of the LDLR protein (p.Gly373Asp). This variant is present in population databases (no rsID available, gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9974426, 11810272, 11933210, 15241806, 21382890, 23375686, 25461735). This variant is also known as p.Gly352Asp. ClinVar contains an entry for this variant (Variation ID: 251673). 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%. This variant disrupts the p.Gly373 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 16159606, 20145306), 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 Natera, Inc., SCV001460269.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004813643.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: LDLR c.1118G>A (p.Gly373Asp), also referred to as p.Gly352Asp, results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-06 in 1613724 control chromosomes (gnomAD). c.1118G>A has been reported in the literature in at least two homozygous individuals and multiple heterozygous individuals affected with Familial Hypercholesterolemia (e.g. Bertolini_1999, Bertolini_2000, Fouchier_2001, Mozas_2004, Di Taranto_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 9974426, 10978268, 34297352, 11810272, 15241806). ClinVar contains an entry for this variant (Variation ID: 251673). Based on the evidence outlined above, the variant was 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: Sep 29, 2024

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