subjects mutated among 2600 FH index cases screened = 4 , family members = 6/previously described in association with FH/Software predictions: Benign
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.2389G>A (p.Val797Met)
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.
(21)
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
21
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.2389G>A (p.Val797Met)
Variation ID: 226393 Accession: VCV000226393.31
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 19p13.2 19: 11128085 (GRCh38) [ NCBI UCSC ] 19: 11238761 (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 May 22, 2016 Sep 16, 2024 Jan 15, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.2389G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Val797Met missense NM_001195798.2:c.2389G>A NP_001182727.1:p.Val797Met missense NM_001195799.2:c.2266G>A NP_001182728.1:p.Val756Met missense NM_001195800.2:c.1885G>A NP_001182729.1:p.Val629Met missense NM_001195803.2:c.1855G>A NP_001182732.1:p.Val619Met missense NC_000019.10:g.11128085G>A NC_000019.9:g.11238761G>A NG_009060.1:g.43705G>A LRG_274:g.43705G>A LRG_274t1:c.2389G>A LRG_274p1:p.Val797Met - Protein change
- V797M, V756M, V629M, V619M
- Other names
- -
- Canonical SPDI
- NC_000019.10:11128084:G:A
-
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.
- -
- 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 |
4085 | 4361 | |
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 (13) |
criteria provided, multiple submitters, no conflicts
|
Jan 18, 2023 | RCV000211628.29 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 15, 2024 | RCV000587818.12 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Oct 5, 2023 | RCV000497399.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 29, 2019 | RCV000844752.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 20, 2021 | RCV002453757.3 |
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: SCV000295967.2
First in ClinVar: Jul 29, 2016 Last updated: Oct 10, 2018 |
Observation 1:
Number of individuals with the variant: 1
Observation 2:
Number of individuals with the variant: 1
Observation 3:
Number of individuals with the variant: 1
Observation 4:
Number of individuals with the variant: 1
Observation 5:
Number of individuals with the variant: 1
Observation 6:
Number of individuals with the variant: 1
Observation 7:
Number of individuals with the variant: 1
Observation 8:
Number of individuals with the variant: 1
Observation 9:
Number of individuals with the variant: 1
Observation 10:
Number of individuals with the variant: 1
Observation 11:
Number of individuals with the variant: 1
Observation 12:
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: SCV000503482.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
subjects mutated among 2600 FH index cases screened = 4 , family members = 6/previously described in association with FH/Software predictions: Benign
Number of individuals with the variant: 4
|
|
|
Likely pathogenic
(Nov 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
|
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation
Additional submitter:
Centre of Molecular Biology and Gene Therapy, University Hospital Brno
Accession: SCV000540866.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017 |
Number of individuals with the variant: 7
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Tendon xanthoma (present) , Corneal arcus (present) , Ischemic stroke (present)
Family history: yes
Age: 6-72 years
Sex: mixed
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
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: SCV000583945.1
First in ClinVar: Apr 08, 2017 Last updated: Apr 08, 2017
Comment:
ACMG Guidelines: Pathogenic (ii)
|
Number of individuals with the variant: 10
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
(Mar 01, 2016)
|
criteria provided, single submitter
Method: research
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory of Genetics and Molecular Cardiology, University of São Paulo
Study: HipercolBrasil
Accession: SCV000588657.1 First in ClinVar: Aug 13, 2017 Last updated: Aug 13, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008247
Observation 2:
Comment on evidence:
Assay description:Htz patients' lymphocytes, RNA assays
Result:
skipping of exon 16 (p.Ala771Valfs*17)
|
|
|
Pathogenic
(Jun 21, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697227.1
First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018 |
Comment:
Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico … (more)
Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcriptionPCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(May 13, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemias
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000904109.1
First in ClinVar: May 20, 2019 Last updated: May 20, 2019 |
Comment:
Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the … (more)
Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the LDLR mRNA (c.2389G>A). This conserved G at the last nucleotide position of an exon is known to play an important role in splicing. Although detailed splice analysis has not been performed for this variant, one study has indicated that this variant causes splicing defect and leads to absent of transcript (PMID: 9763532). A different variant at the same position (c.2389G>T) has been shown to cause an in-frame skipping of exon 16 that encodes the transmembrane domain of the LDLR protein. This demonstrates the importance of the c.2389G nucleotide in the correct splicing at the exon 16-intron 16 splice region. While this variant is rare in the general population (2/246210 chromosomes in the Genome Aggregation Database, gnomAD), it has been reported in 10+ unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 19446849, 20145306, 22698793, 23375686). In addition, this variant has been shown to segregate with disease in 10 members from a Cuban family with familial hypercholesterolemia (PMID: 7649549). Based on available evidence, this variant is classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(May 24, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: yes
Allele origin:
germline
|
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653660.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
Affects splicing, IVS16 ds -1 G>A.
Number of individuals with the variant: 4
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
|
Pathogenic
(Oct 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000589577.4
First in ClinVar: Aug 20, 2017 Last updated: Nov 25, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna … (more)
Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna et al., 2009); Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009); Also known as p.(V776M); This variant is associated with the following publications: (PMID: 16314194, 32759540, 30526649, 34037665, 9763532, 7649549, 11810272, 12436241, 28104544, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 35339733, 34297352, 36229885, 32977124, 32331935, 33740630, 34497632, 35910211, 35913489, 35480308, 28169869, 19446849, 30710474, 33994402, 36991406, 37482509) (less)
|
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|
Likely pathogenic
(Jan 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002022667.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000627033.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). … (more)
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750518671, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7649549, 9763532, 19446849, 20145306, 22698793, 22859806, 23375686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Homozygous familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731742.3
First in ClinVar: Apr 09, 2018 Last updated: Apr 20, 2024 |
Comment:
The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with … (more)
The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with disease in at least 15 affected relatives from 4 families (Pereira, 1995, Mak 1998, Tichy 2012, Bertolini 2013, Setia 2016, Leren 2004). This variant has also been reported in Clinvar (Variation ID 226393). This variant has been identified in 1/30782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750518671). This variant is located in the last base of the exon, which is part of the 5’ splice region and has been shown to cause altered splicing leading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population and the demonstrated impact to the protein. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Suma Genomics
Accession: SCV004041569.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Age: 0-9 years
Sex: female
|
|
|
Pathogenic
(Mar 08, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002047264.2
First in ClinVar: Jan 03, 2022 Last updated: Jan 06, 2024 |
Comment:
This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 … (more)
This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 (2010), 18718593 (2009)). One family study indicated the variant strongly segregated with disease (PMID: 7649549 (1995)). In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)). Based on the available information, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(May 20, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002737317.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at … (more)
The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at nucleotide position 2389. The amino acid change results in valine to methionine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This alteration (also referred to as p.V776M) has been reported in a number of individuals of different origins with familial hypercholesterolemia (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). In addition, this alteration segregated with the disease in a multi-generation family (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22). One study suggested that this alteration would affect the splicing as only the wild type allele was detected by the reverse transcription (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
|
|
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Pathogenic
(Apr 12, 2013)
|
no assertion criteria provided
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital
Accession: SCV000268666.1
First in ClinVar: May 22, 2016 Last updated: May 22, 2016 |
Number of individuals with the variant: 1
|
|
|
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: SCV000606634.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
|
|
Pathogenic
(Jan 01, 2023)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham
Accession: SCV005205811.1
First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16.This variant has been found in … (more)
The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16.This variant has been found in several FH patients including evidence of cosegregation with disease. (less)
Age: 35-65 years
Ethnicity/Population group: Asian- South Indian
|
|
|
Uncertain significance
(Mar 01, 2016)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Familial hypercholesterolemia
Affected status: yes
Allele origin:
germline
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000323009.1
First in ClinVar: Oct 15, 2016 Last updated: Oct 15, 2016 |
Comment:
0/150 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
Observation 1:
Comment on evidence:
%MAF (ExAC):0.0008247
Observation 2:
Comment on evidence:
Heterozygous patients' lymphocytes, RNA assays
Result:
skipping of exon 16 (p.Ala771Valfs*17)
|
|
|
Uncertain significance
(Mar 01, 2016)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Fundacion Hipercolesterolemia Familiar
Study: SAFEHEART
Accession: SCV000607696.1 First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008247
Observation 2:
Comment on evidence:
Htz patients' lymphocytes, RNA assays
Result:
skipping of exon 16 (p.Ala771Valfs*17)
|
|
|
Uncertain significance
(Mar 01, 2016)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Iberoamerican FH Network
Accession: SCV000748063.1
First in ClinVar: May 19, 2018 Last updated: May 19, 2018
Comment:
Variant present in the database from Mexico
|
Observation 1:
Comment on evidence:
%MAF(ExAC):0.0008247
Observation 2:
Comment on evidence:
Assay Description:Htz patients' lymphocytes, RNA assays
Result:
skipping of exon 16 (p.Ala771Valfs*17)
|
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcriptionPCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the LDLR mRNA (c.2389G>A). This conserved G at the last nucleotide position of an exon is known to play an important role in splicing. Although detailed splice analysis has not been performed for this variant, one study has indicated that this variant causes splicing defect and leads to absent of transcript (PMID: 9763532). A different variant at the same position (c.2389G>T) has been shown to cause an in-frame skipping of exon 16 that encodes the transmembrane domain of the LDLR protein. This demonstrates the importance of the c.2389G nucleotide in the correct splicing at the exon 16-intron 16 splice region. While this variant is rare in the general population (2/246210 chromosomes in the Genome Aggregation Database, gnomAD), it has been reported in 10+ unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 19446849, 20145306, 22698793, 23375686). In addition, this variant has been shown to segregate with disease in 10 members from a Cuban family with familial hypercholesterolemia (PMID: 7649549). Based on available evidence, this variant is classified as Pathogenic.
Comment:
Affects splicing, IVS16 ds -1 G>A.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna et al., 2009); Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009); Also known as p.(V776M); This variant is associated with the following publications: (PMID: 16314194, 32759540, 30526649, 34037665, 9763532, 7649549, 11810272, 12436241, 28104544, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 35339733, 34297352, 36229885, 32977124, 32331935, 33740630, 34497632, 35910211, 35913489, 35480308, 28169869, 19446849, 30710474, 33994402, 36991406, 37482509)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750518671, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7649549, 9763532, 19446849, 20145306, 22698793, 22859806, 23375686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with disease in at least 15 affected relatives from 4 families (Pereira, 1995, Mak 1998, Tichy 2012, Bertolini 2013, Setia 2016, Leren 2004). This variant has also been reported in Clinvar (Variation ID 226393). This variant has been identified in 1/30782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750518671). This variant is located in the last base of the exon, which is part of the 5’ splice region and has been shown to cause altered splicing leading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population and the demonstrated impact to the protein.
Comment:
This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 (2010), 18718593 (2009)). One family study indicated the variant strongly segregated with disease (PMID: 7649549 (1995)). In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)). Based on the available information, this variant is classified as pathogenic.
Comment:
The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at nucleotide position 2389. The amino acid change results in valine to methionine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This alteration (also referred to as p.V776M) has been reported in a number of individuals of different origins with familial hypercholesterolemia (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). In addition, this alteration segregated with the disease in a multi-generation family (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22). One study suggested that this alteration would affect the splicing as only the wild type allele was detected by the reverse transcription (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16.This variant has been found in several FH patients including evidence of cosegregation with disease.
Comment:
0/150 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
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:
subjects mutated among 2600 FH index cases screened = 4 , family members = 6/previously described in association with FH/Software predictions: Benign
Comment:
Variant summary: The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16. 2/4 in silico tools predict benign outcome for this variant but 5/5 splice prediction tools predict a significant impact on normal splicing. A reverse transcriptionPCR study indicated that it is likely to cause a donor site splicing error (Mak_1998). This variant was found in 1/121374 control chromosomes (including ExAC) at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0012508). This variant has been found in several FH patients including evidence of cosegregation with disease. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
Pathogenic variant based on current evidence: This variant (also known as p.Val776Met in the mature protein) changes the last nucleotide in exon 16 of the LDLR mRNA (c.2389G>A). This conserved G at the last nucleotide position of an exon is known to play an important role in splicing. Although detailed splice analysis has not been performed for this variant, one study has indicated that this variant causes splicing defect and leads to absent of transcript (PMID: 9763532). A different variant at the same position (c.2389G>T) has been shown to cause an in-frame skipping of exon 16 that encodes the transmembrane domain of the LDLR protein. This demonstrates the importance of the c.2389G nucleotide in the correct splicing at the exon 16-intron 16 splice region. While this variant is rare in the general population (2/246210 chromosomes in the Genome Aggregation Database, gnomAD), it has been reported in 10+ unrelated individuals affected with familial hypercholesterolemia (PMID: 18718593, 19446849, 20145306, 22698793, 23375686). In addition, this variant has been shown to segregate with disease in 10 members from a Cuban family with familial hypercholesterolemia (PMID: 7649549). Based on available evidence, this variant is classified as Pathogenic.
Comment:
Affects splicing, IVS16 ds -1 G>A.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); Published function studies demonstrate decreased residual receptor activity in cultured fibroblasts of FH heterozygotes (Guardamagna et al., 2009); Functional splice studies of a different variant at this same nucleotide position (c.2389 G>T, p.V797L) demonstrate skipping of exon 16, further supporting the functional importance of this nucleotide position (Bourbon et al., 2009); Also known as p.(V776M); This variant is associated with the following publications: (PMID: 16314194, 32759540, 30526649, 34037665, 9763532, 7649549, 11810272, 12436241, 28104544, 29233637, 27816806, 23375686, 21310417, 19318025, 20145306, 20538126, 15199436, 22859806, 22698793, 15701167, 18718593, 29874871, 27821657, 31491741, 31447099, 35339733, 34297352, 36229885, 32977124, 32331935, 33740630, 34497632, 35910211, 35913489, 35480308, 28169869, 19446849, 30710474, 33994402, 36991406, 37482509)
Comment:
This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 797 of the LDLR protein (p.Val797Met). This variant also falls at the last nucleotide of exon 16, which is part of the consensus splice site for this exon. This variant is present in population databases (rs750518671, gnomAD 0.003%). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 7649549, 9763532, 19446849, 20145306, 22698793, 22859806, 23375686). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 226393). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.Val797Met variant in LDLR has been reported in the heterozygous, homozygous, or compound heterozygous state in >10 individuals with familial hypercholesterolemia (FH), segregating with disease in at least 15 affected relatives from 4 families (Pereira, 1995, Mak 1998, Tichy 2012, Bertolini 2013, Setia 2016, Leren 2004). This variant has also been reported in Clinvar (Variation ID 226393). This variant has been identified in 1/30782 South Asian chromosomes by the genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750518671). This variant is located in the last base of the exon, which is part of the 5’ splice region and has been shown to cause altered splicing leading to absent protein (Mak 1998). Heterozygous loss of function of the LDLR gene is an established disease mechanism in FH. In summary, this variant meets our criteria to be classified as pathogenic for familial hypercholesterolemia in an autosomal dominant manner based upon presence in affected individuals, segregation studies, low frequency in the general population and the demonstrated impact to the protein.
Comment:
This variant has been reported in multiple index patients with hypercholesterolemia in the published literature (PMID: 31491741 (2019), 23375686 (2013), 22698793 (2012), 20538126 (2010), 20145306 (2010), 18718593 (2009)). One family study indicated the variant strongly segregated with disease (PMID: 7649549 (1995)). In addition, this variant is located at an exon-intron junction and an RT-PCR study suggests the variant may affect LDLR mRNA splicing (PMID: 9763532 (1998)). Based on the available information, this variant is classified as pathogenic.
Comment:
The c.2389G>A pathogenic mutation (also known as p.V797M), located in coding exon 16 of the LDLR gene, results from a G to A substitution at nucleotide position 2389. The amino acid change results in valine to methionine at codon 797, an amino acid with highly similar properties. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. This alteration (also referred to as p.V776M) has been reported in a number of individuals of different origins with familial hypercholesterolemia (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22; Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5; Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Leren TP et al. Semin Vasc Med, 2004 Feb;4:75-85; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42; Alonso R et al. Clin. Biochem., 2009 Jun;42:899-903; Guardamagna O et al. J. Pediatr., 2009 Aug;155:199-204.e2; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Chiou KR et al. Am. J. Cardiol., 2010 Jun;105:1752-8; Setia N et al. Atherosclerosis, 2016 Dec;255:31-36; Durst R et al. Atherosclerosis, 2017 Feb;257:55-63). In addition, this alteration segregated with the disease in a multi-generation family (Pereira E et al. Hum. Genet., 1995 Sep;96:319-22). One study suggested that this alteration would affect the splicing as only the wild type allele was detected by the reverse transcription (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Comment:
The LDLR c.2389G>A (p.Val797Met) variant involves the alteration of a conserved nucleotide located at the last nucleotide of exon 16.This variant has been found in several FH patients including evidence of cosegregation with disease.
Comment:
0/150 non-FH alleles; 0/100 healthy control individuals; 0/60 healthy control individuals
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Limited-Variant Screening vs Comprehensive Genetic Testing for Familial Hypercholesterolemia Diagnosis. | Sturm AC | JAMA cardiology | 2021 | PMID: 34037665 |
| Molecular genetic testing for autosomal dominant hypercholesterolemia in 29,449 Norwegian index patients and 14,230 relatives during the years 1993-2020. | Leren TP | Atherosclerosis | 2021 | PMID: 33740630 |
| The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia. | Meshkov A | Genes | 2021 | PMID: 33418990 |
| Genetic and Clinical Characteristics of Patients With Homozygous and Compound Heterozygous Familial Hypercholesterolemia From Three Different Populations: Case Series. | Marusic T | Frontiers in genetics | 2020 | PMID: 33093846 |
| Homozygous familial hypercholesterolemia in Italy: Clinical and molecular features. | Bertolini S | Atherosclerosis | 2020 | PMID: 32977124 |
| A catalog of the pathogenic mutations of LDL receptor gene in Japanese familial hypercholesterolemia. | Tada H | Journal of clinical lipidology | 2020 | PMID: 32331935 |
| Impact of LDLR and PCSK9 pathogenic variants in Japanese heterozygous familial hypercholesterolemia patients. | Hori M | Atherosclerosis | 2019 | PMID: 31491741 |
| Harmonizing Clinical Sequencing and Interpretation for the eMERGE III Network. | eMERGE Consortium. Electronic address: [email protected] | American journal of human genetics | 2019 | PMID: 31447099 |
| Lipid profile and genetic status in a familial hypercholesterolemia pediatric population: exploring the LDL/HDL ratio. | Di Taranto MD | Clinical chemistry and laboratory medicine | 2019 | PMID: 30710474 |
| Application of expanded genetic analysis in the diagnosis of familial hypercholesterolemia in patients with very early-onset coronary artery disease. | Cao YX | Journal of translational medicine | 2018 | PMID: 30526649 |
| Molecular genetics of familial hypercholesterolemia in Israel-revisited. | Durst R | Atherosclerosis | 2017 | PMID: 28104544 |
| Spectrum of mutations in homozygous familial hypercholesterolemia in India, with four novel mutations. | Setia N | Atherosclerosis | 2016 | PMID: 27816806 |
| Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. | Bertolini S | Atherosclerosis | 2013 | PMID: 23375686 |
| Genetic mutations in patients with possible familial hypercholesterolaemia in South East Scotland. | Ho CK | Scottish medical journal | 2012 | PMID: 22859806 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| An APEX-based genotyping microarray for the screening of 168 mutations associated with familial hypercholesterolemia. | Dušková L | Atherosclerosis | 2011 | PMID: 21310417 |
| Detection of mutations and large rearrangements of the low-density lipoprotein receptor gene in Taiwanese patients with familial hypercholesterolemia. | Chiou KR | The American journal of cardiology | 2010 | PMID: 20538126 |
| Molecular characterization of Polish patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. | Chmara M | Journal of applied genetics | 2010 | PMID: 20145306 |
| 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 |
| Update of Japanese common LDLR gene mutations and their phenotypes: Mild type mutation L547V might predominate in the Japanese population. | Miyake Y | Atherosclerosis | 2009 | PMID: 18718593 |
| Familial hypercholesterolaemia in Portugal. | Bourbon M | Atherosclerosis | 2008 | PMID: 17765246 |
| Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
| Genetic heterogeneity of autosomal dominant hypercholesterolemia in Mexico. | Robles-Osorio L | Archives of medical research | 2006 | PMID: 16314194 |
| Familial hypercholesterolemia in St-Petersburg: the known and novel mutations found in the low density lipoprotein receptor gene in Russia. | Zakharova FM | BMC medical genetics | 2005 | PMID: 15701167 |
| Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program. | Leren TP | Seminars in vascular medicine | 2004 | PMID: 15199436 |
| 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 |
| The molecular basis of familial hypercholesterolemia in The Netherlands. | Fouchier SW | Human genetics | 2001 | PMID: 11810272 |
| Molecular genetics of familial hypercholesterolemia in Spain: Ten novel LDLR mutations and population analysis. | García-García AB | Human mutation | 2001 | PMID: 11668640 |
| Mutations in the low-density lipoprotein receptor gene in Chinese familial hypercholesterolemia patients. | Mak YT | Arteriosclerosis, thrombosis, and vascular biology | 1998 | PMID: 9763532 |
| Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
| Recurrent and novel LDL receptor gene mutations causing heterozygous familial hypercholesterolemia in La Habana. | Pereira E | Human genetics | 1995 | PMID: 7649549 |
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Text-mined citations for this variant ...
HelpRecord last updated Nov 10, 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.