NM_000527.5(LDLR):c.1012T>G (p.Cys338Gly) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Sep 3, 2023
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:: RCV000589507.9

Allele description [Variation Report for NM_000527.5(LDLR):c.1012T>G (p.Cys338Gly)]

NM_000527.5(LDLR):c.1012T>G (p.Cys338Gly)

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.1012T>G (p.Cys338Gly)

HGVS:

NC_000019.10:g.11110723T>G
NG_009060.1:g.26343T>G
NM_000527.5:c.1012T>GMANE SELECT
NM_001195798.2:c.1012T>G
NM_001195799.2:c.889T>G
NM_001195800.2:c.508T>G
NM_001195803.2:c.631T>G
NP_000518.1:p.Cys338Gly
NP_000518.1:p.Cys338Gly
NP_001182727.1:p.Cys338Gly
NP_001182728.1:p.Cys297Gly
NP_001182729.1:p.Cys170Gly
NP_001182732.1:p.Cys211Gly
LRG_274t1:c.1012T>G
LRG_274:g.26343T>G
LRG_274p1:p.Cys338Gly
NC_000019.9:g.11221399T>G
NM_000527.4:c.1012T>G
c.1012T>G

Protein change:

C170G

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000336; dbSNP: rs879254753

NCBI 1000 Genomes Browser:

rs879254753

Molecular consequence:

NM_000527.5:c.1012T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1012T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.889T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.508T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.631T>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

Taxonomy Links for Nucleotide (Select 1034608066) (1)
Taxonomy
5'-AMP-activated protein kinase subunit gamma-2 isoform X6 [Homo sapiens]
5'-AMP-activated protein kinase subunit gamma-2 isoform X6 [Homo sapiens]
gi|2462614656|ref|XP_054214320.1|

Protein
PREDICTED: Homo sapiens protein kinase AMP-activated non-catalytic subunit gamma...
PREDICTED: Homo sapiens protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2), transcript variant X6, mRNA
gi|2462614655|ref|XM_054358345.1|

Nucleotide
Homo sapiens protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2)...
Homo sapiens protein kinase AMP-activated non-catalytic subunit gamma 2 (PRKAG2), transcript variant 2, mRNA
gi|1890333412|ref|NM_024429.2|

Nucleotide

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
SCV000697179	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 2, 2016)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 21382890, 10735632, 23833242, 15885240, 21310417, 25911074, 15823280 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000909151	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 22, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002309343	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 3, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 15885240, 31345425, 7548065, 7603991, 7979249, 18325082, 8568489, 10735632, 10924730, 24420163, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697179

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 2, 2016)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000909151

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Mar 22, 2019)

germline

clinical testing

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

SCV002309343

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 3, 2023)

germline

clinical testing

PubMed (11)
[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

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

Inheritance pattern of familial hypercholesterolemia and markers of cardiovascular risk.

Kusters DM, Avis HJ, Braamskamp MJ, Huijgen R, Wijburg FA, Kastelein JJ, Wiegman A, Hutten BA.

J Lipid Res. 2013 Sep;54(9):2543-9. doi: 10.1194/jlr.M034538. Epub 2013 Jul 5.

PubMed [citation]

PMID:: 23833242
PMCID:: PMC3735950

See all PubMed Citations (17)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697179.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

Variant summary: The LDLR c.1012T>G (p.Cys338Gly) variant, alternatively also known as C317G, involves the alteration of a conserved nucleotide and is located in the epidermal growth factor (EGR) precursor homology domain of the protein. 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 120874 control chromosomes. The variant has been reported in at least four FH patients in literature including a family where the variant was said to co-segregate with disease (Lombardi_2000, Fard-Esfahani_2005, Donato_2014). This variant is expected to be deleterious as mutations involving Cys residues in this gene are recurrent and may affect folding of the protein (Lombardi_2000, Donato_2014). In addition, multiple reports of variation at LDLR residue p.Cys338 have been reported in FH patients including missense changes of this residue to glycine (Gly), serine (Ser), arginine (Arg), and tyrosine (Tyr), as well as a nonsense change (p.Cys338X), suggesting a notion that this residue is mutational hot-spot. Functional studies have shown that binding, uptake, and degradation of iodinated LDL in skin fibroblasts from a patient homozygous for p.Cys338Tyr variant was <10% of normal (reviewed by Donato_2014). Furthermore, one research institution in ClinVar has classified the variant as likely pathogenic. Taken together, this variant is currently classified as likely 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, SCV000909151.3

#	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.Cys317Gly in the mature protein) is located in the EGF-like repeat A of the EGF precursor homology domain of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. Although functional assays have not been performed, this variant changes one of the functionally critical cysteine residues that form intra-repeat disulfide bonds in the EGF precursor homology domain (PMID: 3495735, 4750422) and is expected to have deleterious impact on the LDLR protein folding and stability. This variant has been reported in two Dutch individuals with hypercholesterolemia (PMID: 10735632, 21382890) and in a dyslipidemic patient undergoing LDL apheresis (PMID: 24420163). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different missense variants at the same position (Cys338Ser, Cys338Arg, Cys338Tyr) have been reported in individuals affected with familial hypercholesterolemia. Based on available evidence, this variant is classified as Likely 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002309343.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 338 of the LDLR protein (p.Cys338Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10735632, 15885240, 24420163, 31345425). This variant is also known as C317G. ClinVar contains an entry for this variant (Variation ID: 251594). 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. This variant affects a cysteine residue located within an LDLRA or epidermal-growth-factor (EGF)-like domains of the LDLR protein. Cysteine residues in these domains have been shown to be involved in the formation of disulfide bridges, which are critical for protein structure and stability (PMID: 7548065, 7603991, 7979249). In addition, missense substitutions within the LDLRA and EGF-like domains affecting cysteine residues are overrepresented among patients with hypercholesterolemia (PMID: 18325082). This variant disrupts the p.Cys338 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 8568489, 10735632, 10924730, 24420163), 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

Last Updated: Sep 29, 2024

ClinVar

Relating variation to medicine