subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH and functional study "GFP fused protein not transported to cell surface"/software prediction damaging
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1730G>C (p.Trp577Ser)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000527.5(LDLR):c.1730G>C (p.Trp577Ser)
Variation ID: 252003 Accession: VCV000252003.15
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11116883 (GRCh38) [ NCBI UCSC ] 19: 11227559 (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 Oct 8, 2024 Oct 5, 2022 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1730G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Trp577Ser missense NM_001195798.2:c.1730G>C NP_001182727.1:p.Trp577Ser missense NM_001195799.2:c.1607G>C NP_001182728.1:p.Trp536Ser missense NM_001195800.2:c.1226G>C NP_001182729.1:p.Trp409Ser missense NM_001195803.2:c.1349G>C NP_001182732.1:p.Trp450Ser missense NC_000019.10:g.11116883G>C NC_000019.9:g.11227559G>C NG_009060.1:g.32503G>C LRG_274:g.32503G>C LRG_274t1:c.1730G>C LRG_274p1:p.Trp577Ser P01130:p.Trp577Ser - Protein change
- W577S, W409S, W536S, W450S
- Other names
- -
- Canonical SPDI
- NC_000019.10:11116882:G: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.
-
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
- 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 15, 2021 | RCV000238353.7 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 20, 2020 | RCV001377886.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 5, 2022 | RCV002401945.2 | |
|
LDLR-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Nov 22, 2023 | RCV003897581.2 |
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 13, 2022 | RCV004696891.1 |
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. |
|
|---|---|---|---|---|---|
|
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: SCV000295620.2
First in ClinVar: Jul 29, 2016 Last updated: May 03, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Dec 16, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix
Accession: SCV000503400.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Comment:
subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH and functional study "GFP fused protein not transported … (more)
subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH and functional study "GFP fused protein not transported to cell surface"/software prediction damaging (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 30, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial Hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille
Accession: SCV000583872.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016
Comment:
ACMG Guidelines: Pathogenic (i)
|
Number of individuals with the variant: 7
Clinical Features:
Hyperbetalipoproteinemia (present) , Hypercholesterolemia (present)
Indication for testing: Familial Hypercholesterolemia
Sex: mixed
Geographic origin: France
Comment on evidence:
Dutch Lipid Clinic Scoring : Definite FH
Secondary finding: no
|
|
|
Likely pathogenic
(Dec 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579828.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS4, PM5, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Likely pathogenic
(Sep 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001575334.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (rs138947766, ExAC 0.001%). This variant has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 8697568, 11810272, … (more)
This variant is present in population databases (rs138947766, ExAC 0.001%). This variant has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 8697568, 11810272, Invitae). This variant is also known as W556S. ClinVar contains an entry for this variant (Variation ID: 252003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 28126585, 27919346, 11916007, 27294413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces tryptophan with serine at codon 577 of the LDLR protein (p.Trp577Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. (less)
|
|
|
Pathogenic
(Oct 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002713860.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.W577S pathogenic mutation (also known as c.1730G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at … (more)
The p.W577S pathogenic mutation (also known as c.1730G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1730. The tryptophan at codon 577 is replaced by serine, an amino acid with highly dissimilar properties. This alteration impacts the YWTD motif in LDLR class B repeat five. This variant has been detected in multiple individuals with familial hypercholesterolemia (FH) and has been shown to be a founder mutation responsible for ~12% of Danish FH cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Jensen HK et al. Atherosclerosis, 1997 May;131:67-72). Functional studies indicate that this alteration causes a trafficking defect (Jensen HK et al. Atherosclerosis, 1997 May;131:67-72), Another pathogenic mutation, p.W577R, has been described in the same codon (Gutierrez G et al. Hum. Mutat., 2000 Oct;16:374). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Jul 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005198659.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum
Accession: SCV000606501.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Nov 22, 2023)
|
no assertion criteria provided
Method: clinical testing
|
LDLR-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004711912.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The LDLR c.1730G>C variant is predicted to result in the amino acid substitution p.Trp577Ser. This variant (also known as W556S) was reported in individuals with … (more)
The LDLR c.1730G>C variant is predicted to result in the amino acid substitution p.Trp577Ser. This variant (also known as W556S) was reported in individuals with autosomal dominant familial hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Table S1, Benedek et al. 2021. PubMed ID: 33955087; Table S1, Leren et al. 2021. PubMed ID: 33740630; Table 2, Miroshnikova et al. 2021. PubMed ID: 33269076). Other missense variants impacting this residue (p.Trp577Gly, p.Trp577Cys, p.Trp577Arg) have also been reported as pathogenic in individuals with hypercholesterolemia phenotypes (Table S1, Leren et al. 2021. PubMed ID: 33740630; eTable 1, Sturm. 2021. PubMed ID: 34037665). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
This variant is present in population databases (rs138947766, ExAC 0.001%). This variant has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 8697568, 11810272, Invitae). This variant is also known as W556S. ClinVar contains an entry for this variant (Variation ID: 252003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 28126585, 27919346, 11916007, 27294413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces tryptophan with serine at codon 577 of the LDLR protein (p.Trp577Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine.
Comment:
The p.W577S pathogenic mutation (also known as c.1730G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1730. The tryptophan at codon 577 is replaced by serine, an amino acid with highly dissimilar properties. This alteration impacts the YWTD motif in LDLR class B repeat five. This variant has been detected in multiple individuals with familial hypercholesterolemia (FH) and has been shown to be a founder mutation responsible for ~12% of Danish FH cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Jensen HK et al. Atherosclerosis, 1997 May;131:67-72). Functional studies indicate that this alteration causes a trafficking defect (Jensen HK et al. Atherosclerosis, 1997 May;131:67-72), Another pathogenic mutation, p.W577R, has been described in the same codon (Gutierrez G et al. Hum. Mutat., 2000 Oct;16:374). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The LDLR c.1730G>C variant is predicted to result in the amino acid substitution p.Trp577Ser. This variant (also known as W556S) was reported in individuals with autosomal dominant familial hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Table S1, Benedek et al. 2021. PubMed ID: 33955087; Table S1, Leren et al. 2021. PubMed ID: 33740630; Table 2, Miroshnikova et al. 2021. PubMed ID: 33269076). Other missense variants impacting this residue (p.Trp577Gly, p.Trp577Cys, p.Trp577Arg) have also been reported as pathogenic in individuals with hypercholesterolemia phenotypes (Table S1, Leren et al. 2021. PubMed ID: 33740630; eTable 1, Sturm. 2021. PubMed ID: 34037665). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
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:
subject mutated among 2600 FH index cases screened = 1 / previously described in association with FH and functional study "GFP fused protein not transported to cell surface"/software prediction damaging
Comment:
This variant is present in population databases (rs138947766, ExAC 0.001%). This variant has been observed in individual(s) with autosomal dominant familial hypercholesterolemia (PMID: 8697568, 11810272, Invitae). This variant is also known as W556S. ClinVar contains an entry for this variant (Variation ID: 252003). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Trp577 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11013454, 12436241, 15823276, 17347910, 18339137, 22528129, 28126585, 27919346, 11916007, 27294413). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces tryptophan with serine at codon 577 of the LDLR protein (p.Trp577Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine.
Comment:
The p.W577S pathogenic mutation (also known as c.1730G>C), located in coding exon 12 of the LDLR gene, results from a G to C substitution at nucleotide position 1730. The tryptophan at codon 577 is replaced by serine, an amino acid with highly dissimilar properties. This alteration impacts the YWTD motif in LDLR class B repeat five. This variant has been detected in multiple individuals with familial hypercholesterolemia (FH) and has been shown to be a founder mutation responsible for ~12% of Danish FH cases (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Jensen HK et al. Atherosclerosis, 1997 May;131:67-72). Functional studies indicate that this alteration causes a trafficking defect (Jensen HK et al. Atherosclerosis, 1997 May;131:67-72), Another pathogenic mutation, p.W577R, has been described in the same codon (Gutierrez G et al. Hum. Mutat., 2000 Oct;16:374). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The LDLR c.1730G>C variant is predicted to result in the amino acid substitution p.Trp577Ser. This variant (also known as W556S) was reported in individuals with autosomal dominant familial hypercholesterolemia (Fouchier et al. 2001. PubMed ID: 11810272; Table S1, Benedek et al. 2021. PubMed ID: 33955087; Table S1, Leren et al. 2021. PubMed ID: 33740630; Table 2, Miroshnikova et al. 2021. PubMed ID: 33269076). Other missense variants impacting this residue (p.Trp577Gly, p.Trp577Cys, p.Trp577Arg) have also been reported as pathogenic in individuals with hypercholesterolemia phenotypes (Table S1, Leren et al. 2021. PubMed ID: 33740630; eTable 1, Sturm. 2021. PubMed ID: 34037665). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Homozygous familial hypercholesterolemia: Summarized case reports. | Widhalm K | Atherosclerosis | 2017 | PMID: 28126585 |
| Disease control via intensified lipoprotein apheresis in three siblings with familial hypercholesterolemia. | Taylan C | Journal of clinical lipidology | 2016 | PMID: 27919346 |
| Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016. | Srivastava AK | Human genomics | 2016 | PMID: 27294413 |
| Pharmacogenetic aspects in familial hypercholesterolemia with the special focus on FHMarburg (FH p.W556R). | Schaefer JR | Clinical research in cardiology supplements | 2012 | PMID: 22528129 |
| Liver transplantation in a subject with familial hypercholesterolemia carrying the homozygous p.W577R LDL-receptor gene mutation. | Schmidt HH | Clinical transplantation | 2008 | PMID: 18339137 |
| Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations. | Widhalm K | Journal of inherited metabolic disease | 2007 | PMID: 17347910 |
| The molecular basis of familial hypercholesterolaemia in Turkish patients. | Sözen MM | Atherosclerosis | 2005 | PMID: 15823276 |
| Intronic mutations outside of Alu-repeat-rich domains of the LDL receptor gene are a cause of familial hypercholesterolemia. | Amsellem S | Human genetics | 2002 | PMID: 12436241 |
| Eight novel mutations and functional impairments of the LDL receptor in familial hypercholesterolemia in the north of Japan. | Hattori H | Journal of human genetics | 2002 | PMID: 11916007 |
| The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
| Homozygous familial hypercholesterolemia: A novel point mutation (W556R) in a Turkish patient. | Gutierrez G | Human mutation | 2000 | PMID: 11013454 |
| Spectrum of LDL receptor gene mutations in Denmark: implications for molecular diagnostic strategy in heterozygous familial hypercholesterolemia. | Jensen HK | Atherosclerosis | 1999 | PMID: 10532689 |
| A common W556S mutation in the LDL receptor gene of Danish patients with familial hypercholesterolemia encodes a transport-defective protein. | Jensen HK | Atherosclerosis | 1997 | PMID: 9180246 |
| High sensitivity of the single-strand conformation polymorphism method for detecting sequence variations in the low-density lipoprotein receptor gene validated by DNA sequencing. | Jensen HK | Clinical chemistry | 1996 | PMID: 8697568 |
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Text-mined citations for rs138947766 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 13, 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.