For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This variant has been observed to segregate with familial hypercholesterolemia in multiple families (PMID: 1634609, 9409302). This variant is also known as a founder mutation FH-North Karelia in the literature. ClinVar contains an entry for this variant (Variation ID: 3729). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro309Lysfs*59) in the LDLR gene. It is expected to result in an absent or disrupted protein product.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.925_931del (p.Pro309fs)
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.
(6)
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
6
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.925_931del (p.Pro309fs)
Variation ID: 3729 Accession: VCV000003729.10
- Type and length
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Deletion, 7 bp
- Location
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Cytogenetic: 19p13.2 19: 11107498-11107504 (GRCh38) [ NCBI UCSC ] 19: 11218175-11218181 (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 Apr 4, 2013 Nov 24, 2024 May 31, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.925_931del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Pro309fs frameshift NM_000527.4:c.925_931delCCCATCA frameshift NM_001195798.2:c.925_931del NP_001182727.1:p.Pro309fs frameshift NM_001195799.2:c.802_808del NP_001182728.1:p.Pro268fs frameshift NM_001195800.2:c.421_427del NP_001182729.1:p.Pro141fs frameshift NM_001195803.2:c.544_550del NP_001182732.1:p.Pro182fs frameshift NC_000019.10:g.11107499_11107505del NC_000019.9:g.11218175_11218181del NG_009060.1:g.23119_23125del LRG_274:g.23119_23125del - Protein change
- P309fs, P141fs, P182fs, P268fs
- Other names
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FH North Karelia
p.Pro309Lysfs*59
- Canonical SPDI
- NC_000019.10:11107497:ACCCATCA:A
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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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 25, 2016 | RCV000003927.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2019 | RCV000810136.9 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 31, 2024 | RCV004791195.1 |
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. |
|
|---|---|---|---|---|---|
|
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: SCV000295060.2
First in ClinVar: Jul 29, 2016 Last updated: Sep 30, 2017 |
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
|
|
|
Pathogenic
(Mar 01, 2016)
|
criteria provided, single submitter
Method: curation, literature only
|
Familial hypercholesterolemia
(Autosomal dominant inheritance)
Affected status: unknown, not applicable
Allele origin:
germline,
not applicable
|
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge
Accession: SCV000599351.1
First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017 |
Observation 1: Observation 2:
Comment on evidence:
Assay Description:Htz patients' fibroblasts, 125-I LDL and RNA assays
Result:
only 5% of mutant RNA; 50% LDL-LDLR binding, 41% LDL-LDLR uptake; 42% degradation
|
|
|
Pathogenic
(Jan 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000950326.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This variant has been … (more)
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This variant has been observed to segregate with familial hypercholesterolemia in multiple families (PMID: 1634609, 9409302). This variant is also known as a founder mutation FH-North Karelia in the literature. ClinVar contains an entry for this variant (Variation ID: 3729). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro309Lysfs*59) in the LDLR gene. It is expected to result in an absent or disrupted protein product. (less)
|
|
|
Pathogenic
(May 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413307.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PS4, PVS1
Number of individuals with the variant: 1
|
|
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Pathogenic
(Nov 01, 1997)
|
no assertion criteria provided
Method: literature only
|
FH NORTH KARELIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024092.2
First in ClinVar: Apr 04, 2013 Last updated: Jun 23, 2019 |
Comment on evidence:
Koivisto et al. (1992) identified a mutation found in many Finnish patients with heterozygous FH (FHCL1; 143890). The mutation, designated FH North Karelia (FH-NK) , … (more)
Koivisto et al. (1992) identified a mutation found in many Finnish patients with heterozygous FH (FHCL1; 143890). The mutation, designated FH North Karelia (FH-NK) , deleted 7 nucleotides from exon 6 of the LDLR gene, caused a translational frameshift, and was predicted to result in a truncated receptor protein. The mutation was found in 69 (34%) of 201 unrelated Finnish FH patients and was especially frequent (prevalence 79%) in patients from eastern Finland. FH Helsinki (606945.0029) and FH North Karelia together account for about two-thirds of FH mutations in Finland. In Finnish North Karelia, with a population of about 180,000, Vuorio et al. (1997) found that the FH-NK mutation accounts for 84% (340 of 407) of FH cases, while the FH-Helsinki allele was found in 4% (18 cases). The minimum prevalence of FH in North Karelia was estimated to be 1 in 441 inhabitants; in 1 commune, a frequency of 1 in 143 was found. By use of parish and tax records, they identified a common ancestor for most of the North Karelian FH-NK persons in the village of Puso, located within an area where the FH prevalence is the highest. DNA analysis indicated that 2% of subjects aged 1 to 25 years would have been diagnosed as false-negative and 7% as false-positive FH patients on the basis of LDL cholesterol determinations alone. Coronary heart disease (CHD) was present in 65 (30%) of the 179 FH gene carriers aged 25 years or more, and 19 individuals had a previous history of acute myocardial infarction. The average age at onset of CHD was 42 years for males and 48 years for females. (less)
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|
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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: SCV000606271.1
First in ClinVar: Sep 30, 2017 Last updated: Sep 30, 2017 |
|
Comment:
Comment:
PS4, PVS1
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:
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). This variant has been observed to segregate with familial hypercholesterolemia in multiple families (PMID: 1634609, 9409302). This variant is also known as a founder mutation FH-North Karelia in the literature. ClinVar contains an entry for this variant (Variation ID: 3729). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Pro309Lysfs*59) in the LDLR gene. It is expected to result in an absent or disrupted protein product.
Comment:
PS4, PVS1
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 |
| Founder effects facilitate the use of a genotyping-based approach to molecular diagnosis in Swedish patients with familial hypercholesterolaemia. | Benedek P | Journal of internal medicine | 2021 | PMID: 33955087 |
| 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 |
| Molecular spectrum of autosomal dominant hypercholesterolemia in France. | Marduel M | Human mutation | 2010 | PMID: 20809525 |
| 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 |
| Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study. | Vuorio AF | Arteriosclerosis, thrombosis, and vascular biology | 1997 | PMID: 9409302 |
| The familial hypercholesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland. | Koivisto UM | The Journal of clinical investigation | 1992 | PMID: 1634609 |
Text-mined citations for rs387906304 ...
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 Nov 25, 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.