NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 19, 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:: RCV000588581.13

Allele description [Variation Report for NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)]

NM_000527.5(LDLR):c.974G>A (p.Cys325Tyr)

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.974G>A (p.Cys325Tyr)

Other names:

NM_000527.5(LDLR):c.974G>A; p.Cys325Tyr

HGVS:

NC_000019.10:g.11110685G>A
NG_009060.1:g.26305G>A
NM_000527.5:c.974G>AMANE SELECT
NM_001195798.2:c.974G>A
NM_001195799.2:c.851G>A
NM_001195800.2:c.470G>A
NM_001195803.2:c.593G>A
NP_000518.1:p.Cys325Tyr
NP_000518.1:p.Cys325Tyr
NP_001182727.1:p.Cys325Tyr
NP_001182728.1:p.Cys284Tyr
NP_001182729.1:p.Cys157Tyr
NP_001182732.1:p.Cys198Tyr
LRG_274t1:c.974G>A
LRG_274:g.26305G>A
LRG_274p1:p.Cys325Tyr
NC_000019.9:g.11221361G>A
NM_000527.4:c.974G>A
c.974G>A
p.(Cys325Tyr)

Protein change:

C157Y

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001893; dbSNP: rs879254746

NCBI 1000 Genomes Browser:

rs879254746

Molecular consequence:

NM_000527.5:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.851G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.470G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.593G>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
SCV000697256	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jun 19, 2024)	germline	clinical testing	PubMed (16) [See all records that cite these PMIDs] 19318025, 21865347, 29874871, 31947532, 31491741, 32977124, 33418990, 33079599, 34297352, 30526649, 34496902, 33533259, 28353356, 31345425, 32759540, 35929461 Citation Link,
SCV001544522	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 21865347, 30526649, 32759540, 32977124, 33418990, 7548065, 7603991, 7979249, 18325082, 26802169, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000697256

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jun 19, 2024)

germline

clinical testing

PubMed (16)
[See all records that cite these PMIDs]

Citation Link,

SCV001544522

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 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

Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform.

Alonso R, Defesche JC, Tejedor D, Castillo S, Stef M, Mata N, Gomez-Enterria P, Martinez-Faedo C, Forga L, Mata P.

Clin Biochem. 2009 Jun;42(9):899-903. doi: 10.1016/j.clinbiochem.2009.01.017. Epub 2009 Feb 6.

PubMed [citation]

PMID:: 19318025

Validation of LDLr Activity as a Tool to Improve Genetic Diagnosis of Familial Hypercholesterolemia: A Retrospective on Functional Characterization of LDLr Variants.

Benito-Vicente A, Uribe KB, Jebari S, Galicia-Garcia U, Ostolaza H, Martin C.

Int J Mol Sci. 2018 Jun 5;19(6). doi:pii: E1676. 10.3390/ijms19061676. Review.

PubMed [citation]

PMID:: 29874871
PMCID:: PMC6032215

See all PubMed Citations (22)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697256.4

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

Description

Variant summary: LDLR c.974G>A (p.Cys325Tyr) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Cys325 is a highly conserved residue located in the EGF-like calcium-binding domain of the LDL receptor, HGMD lists >50 Cys missense mutations reported in the literature as associated with hypercholesterolaemia, and five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251090 control chromosomes. .974G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia and coronary artery disease (e.g. Romano_2011, Alonso_2009, Rubba_2017, Cao_2018, Trinder_2019, Hori_2019, Di Taranto_2020, Wang_2020, Bertolini_2020, Doi_2021), including at least two homozygotes. One homozygous patient had this variant in cis with c.(940+1_941-1)_(2311+1_2312-1)dup (Gly314_Gln770dup, exon 7-15 duplication, described as pathogenic) (Di Taranto_2020). These data indicate that the variant may be associated with disease. Two functional studies report experimental evidence evaluating an impact of the variant on protein function and have shown it to have significantly decreased LDLR residual activity in EBV-transformed B-lymphocytes and stimulated T-lymphocytes (Romano_2011, Bertolini_2020). The following publications have been ascertained in the context of this evaluation (PMID: 19318025, 21865347, 29874871, 31947532, 31491741, 32977124, 33418990, 33079599, 34297352, 30526649, 34496902, 33533259, 28353356, 31345425, 32759540, 35929461). ClinVar contains an entry for this variant (Variation ID: 251580). Based on the evidence outlined above, the variant was 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, SCV001544522.4

#	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 tyrosine, which is neutral and polar, at codon 325 of the LDLR protein (p.Cys325Tyr). 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: 21865347, 30526649, 32759540, 32977124, 33418990; Invitae). ClinVar contains an entry for this variant (Variation ID: 251580). 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.Cys325 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26802169). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Oct 8, 2024

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