The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) 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: PP3: REVEL = 0.773. PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1). PP4, PS4 not applicable: Variant did not meet PM2. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Uncertain significance
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.2375T>C (p.Ile792Thr)
Variation ID: 252295 Accession: VCV000252295.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11128071 (GRCh38) [ NCBI UCSC ] 19: 11238747 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jul 29, 2016 May 1, 2024 Aug 26, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2375T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Ile792Thr missense NM_001195798.2:c.2375T>C NP_001182727.1:p.Ile792Thr missense NM_001195799.2:c.2252T>C NP_001182728.1:p.Ile751Thr missense NM_001195800.2:c.1871T>C NP_001182729.1:p.Ile624Thr missense NM_001195803.2:c.1841T>C NP_001182732.1:p.Ile614Thr missense NC_000019.10:g.11128071T>C NC_000019.9:g.11238747T>C NG_009060.1:g.43691T>C LRG_274:g.43691T>C LRG_274t1:c.2375T>C LRG_274p1:p.Ile792Thr - Protein change
- I792T, I624T, I751T, I614T
- Other names
-
NM_000527.5(LDLR):c.2375T>C
p.Ile792Thr
- Canonical SPDI
- NC_000019.10:11128070:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00011
Exome Aggregation Consortium (ExAC) 0.00007
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| LDLR | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4076 | 4352 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Uncertain significance (6) |
reviewed by expert panel
|
Aug 26, 2022 | RCV000238445.9 | |
| Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
|
Nov 5, 2021 | RCV001558972.3 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
May 4, 2022 | RCV002247687.1 | |
| Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 12, 2024 | RCV001523921.7 | |
| Uncertain significance (1) |
criteria provided, single submitter
|
Jul 20, 2023 | RCV003372668.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Aug 26, 2022)
|
reviewed by expert panel
Method: curation
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV002817152.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
Comment:
The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by … (more)
The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) 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: PP3: REVEL = 0.773. PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1). PP4, PS4 not applicable: Variant did not meet PM2. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met. (less)
|
|
|
Likely pathogenic
(Mar 25, 2016)
|
criteria provided, single submitter
Method: literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
LDLR-LOVD, British Heart Foundation
Accession: SCV000295964.2
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
|
Uncertain significance
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607695.1 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment on evidence:
%MAF(ExAC):0.006595
|
|
|
Uncertain significance
(May 04, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001781020.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Comment:
Reported in association with familial hypercholesterolemia (Guardamagna et al., 2009; Alonso et al., 2009); In silico analysis supports that this missense variant has a deleterious … (more)
Reported in association with familial hypercholesterolemia (Guardamagna et al., 2009; Alonso et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 19318025, 19446849, 23375686) (less)
|
|
|
Uncertain significance
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: yes
Allele origin:
germline
|
AiLife Diagnostics, AiLife Diagnostics
Accession: SCV002502948.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Number of individuals with the variant: 1
Secondary finding: no
|
|
|
Uncertain significance
(May 04, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Mendelics
Accession: SCV002518185.1
First in ClinVar: May 28, 2022 Last updated: May 28, 2022 |
|
|
|
Uncertain significance
(Jun 04, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Accession: SCV002764284.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is … (more)
The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is found with low frequency in gnomAD(v2.1.1)(29 heterozygotes, 0 homozygotes; allele frequency: 1.03e-4), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.024) and Pathogenic (REVEL; score:0.773) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance as well as Likely Pathogenic (VarID:252295), and has been reported in individuals with hypercholesterolemia [PMID:19446849, 18096825, 19318025, 23375686], and has also been identified in healthy unaffected individuals [PMID:32719484]. The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance. (less)
Clinical Features:
Coronary artery atherosclerosis (present)
Secondary finding: no
|
|
|
Uncertain significance
(Feb 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV003816532.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
|
|
|
Uncertain significance
(Jan 12, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003269197.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). This variant is present in population databases (rs764493597, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 18096825, 19446849, 23375686, 34456049, 35913489). ClinVar contains an entry for this variant (Variation ID: 252295). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain significance
(May 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV001733661.2
First in ClinVar: Jun 19, 2021 Last updated: Feb 14, 2024 |
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
|
|
|
Uncertain Significance
(Jan 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Semidominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004820676.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests … (more)
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests that this variant may have 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686), as well as in healthy individuals (PMID: 32719484). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 10
|
|
|
Uncertain significance
(Jul 20, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV004087580.2
First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024 |
Comment:
The p.I792T variant (also known as c.2375T>C), located in coding exon 16 of the LDLR gene, results from a T to C substitution at nucleotide … (more)
The p.I792T variant (also known as c.2375T>C), located in coding exon 16 of the LDLR gene, results from a T to C substitution at nucleotide position 2375. The isoleucine at codon 792 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
|
|
|
Uncertain significance
(Jan 14, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086876.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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Comment:
Comment:
Reported in association with familial hypercholesterolemia (Guardamagna et al., 2009; Alonso et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 19318025, 19446849, 23375686)
Comment:
The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is found with low frequency in gnomAD(v2.1.1)(29 heterozygotes, 0 homozygotes; allele frequency: 1.03e-4), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.024) and Pathogenic (REVEL; score:0.773) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance as well as Likely Pathogenic (VarID:252295), and has been reported in individuals with hypercholesterolemia [PMID:19446849, 18096825, 19318025, 23375686], and has also been identified in healthy unaffected individuals [PMID:32719484]. The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). This variant is present in population databases (rs764493597, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 18096825, 19446849, 23375686, 34456049, 35913489). ClinVar contains an entry for this variant (Variation ID: 252295). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests that this variant may have 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686), as well as in healthy individuals (PMID: 32719484). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.I792T variant (also known as c.2375T>C), located in coding exon 16 of the LDLR gene, results from a T to C substitution at nucleotide position 2375. The isoleucine at codon 792 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
The NM_000527.5 (LDLR):c.2375T>C (p. Ile792Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) 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: PP3: REVEL = 0.773. PM2 not met: PopMax MAF = 0.00056 in Latino population in gnomAD (gnomAD version: 2.1.1). PP4, PS4 not applicable: Variant did not meet PM2. PS3 not met: Functional data is not available. PM5 not met: There is one other variant in the same codon: LDLR: NM_000527:c.2374A>T (p.Ile792Phe) is classified as Uncertain significance - insufficient evidence by these guidelines. Therefore PM5 is not met.
Comment:
Reported in association with familial hypercholesterolemia (Guardamagna et al., 2009; Alonso et al., 2009); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32719484, 19318025, 19446849, 23375686)
Comment:
The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene substitutes a well conserved Isoleucine for Threonine at amino acid 792/861 (exon 16/18). This variant is found with low frequency in gnomAD(v2.1.1)(29 heterozygotes, 0 homozygotes; allele frequency: 1.03e-4), suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.024) and Pathogenic (REVEL; score:0.773) to the function of the canonical transcript. This variant is reported in ClinVar as both a Variant of Uncertain Significance as well as Likely Pathogenic (VarID:252295), and has been reported in individuals with hypercholesterolemia [PMID:19446849, 18096825, 19318025, 23375686], and has also been identified in healthy unaffected individuals [PMID:32719484]. The c.2375T>C (p.Ile792Thr) variant identified in the LDLR gene is reported as a Variant of UncertainSignificance.
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 792 of the LDLR protein (p.Ile792Thr). This variant is present in population databases (rs764493597, gnomAD 0.06%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 18096825, 19446849, 23375686, 34456049, 35913489). ClinVar contains an entry for this variant (Variation ID: 252295). 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%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
This missense variant (also known as p.Ile771Thr in the mature protein) replaces isoleucine with threonine at codon 792 of the LDLR protein. Computational prediction suggests that this variant may have 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 variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 19318025, 19446849, 23375686), as well as in healthy individuals (PMID: 32719484). This variant has been identified in 29/282798 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Comment:
The p.I792T variant (also known as c.2375T>C), located in coding exon 16 of the LDLR gene, results from a T to C substitution at nucleotide position 2375. The isoleucine at codon 792 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in familial hypercholesterolemia (FH) cohorts; however, clinical details were limited (Guardamagna O et al. J Pediatr, 2009 Aug;155:199-204.e2; Junyent M et al. Arterioscler Thromb Vasc Biol, 2008 Mar;28:580-6; Alonso R et al. Clin Biochem, 2009 Jun;42:899-903; Bertolini S et al. Atherosclerosis, 2013 Apr;227:342-8; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Universal screening for familial hypercholesterolemia in 2 populations. | Sustar U | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 35913489 |
| Lipoprotein(a) in hereditary hypercholesterolemia: Influence of the genetic cause, defective gene and type of mutation. | Marco-Benedí V | Atherosclerosis | 2022 | PMID: 34456049 |
| Population genetic screening efficiently identifies carriers of autosomal dominant diseases. | Grzymski JJ | Nature medicine | 2020 | PMID: 32719484 |
| Homozygous Familial Hypercholesterolemia in Spain: Prevalence and Phenotype-Genotype Relationship. | Sánchez-Hernández RM | Circulation. Cardiovascular genetics | 2016 | PMID: 27784735 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| The type of LDLR gene mutation predicts cardiovascular risk in children with familial hypercholesterolemia. | Guardamagna O | The Journal of pediatrics | 2009 | PMID: 19446849 |
| Genetic diagnosis of familial hypercholesterolemia using a DNA-array based platform. | Alonso R | Clinical biochemistry | 2009 | PMID: 19318025 |
| Femoral atherosclerosis in heterozygous familial hypercholesterolemia: influence of the genetic defect. | Junyent M | Arteriosclerosis, thrombosis, and vascular biology | 2008 | PMID: 18096825 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/08edf0a6-3b51-4484-b172-bc1e18ae8e44 | - | - | - | - |
Text-mined citations for rs764493597 ...
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Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.