For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 16159606, 22698793), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change decreases LDL binding and uptake (PMID: 28645073). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15701167, 27824480, 28645073, 22698793, Invitae. This variant is also known as p.D601N in the literature. ClinVar contains an entry for this variant (Variation ID: 252092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 622 of the LDLR protein (p.Asp622Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.
ClinVar Genomic variation as it relates to human health
NM_000527.5(LDLR):c.1864G>A (p.Asp622Asn)
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.
(4)
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
4
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.1864G>A (p.Asp622Asn)
Variation ID: 252092 Accession: VCV000252092.10
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.2 19: 11120110 (GRCh38) [ NCBI UCSC ] 19: 11230786 (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 Mar 30, 2024 Feb 23, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000527.5:c.1864G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000518.1:p.Asp622Asn missense NM_001195798.2:c.1864G>A NP_001182727.1:p.Asp622Asn missense NM_001195799.2:c.1741G>A NP_001182728.1:p.Asp581Asn missense NM_001195800.2:c.1360G>A NP_001182729.1:p.Asp454Asn missense NM_001195803.2:c.1483G>A NP_001182732.1:p.Asp495Asn missense NC_000019.10:g.11120110G>A NC_000019.9:g.11230786G>A NG_009060.1:g.35730G>A LRG_274:g.35730G>A LRG_274t1:c.1864G>A LRG_274p1:p.Asp622Asn - Protein change
- D622N, D581N, D454N, D495N
- Other names
- -
- Canonical SPDI
- NC_000019.10:11120109:G: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 |
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. |
|---|---|---|---|---|
| Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 23, 2024 | RCV000238037.3 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Sep 4, 2018 | RCV000812951.8 |
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: SCV000295725.2
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
|
|
|
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: SCV000540846.1
First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016 |
Number of individuals with the variant: 3
Clinical Features:
Hypercholesterolemia (present)
Family history: yes
Age: 16-44 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: Czech Republic
Tissue: Whole blood
|
|
|
Pathogenic
(Sep 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Familial hypercholesterolemia
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000953281.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 16159606, 22698793), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change decreases LDL binding and uptake (PMID: 28645073). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15701167, 27824480, 28645073, 22698793, Invitae. This variant is also known as p.D601N in the literature. ClinVar contains an entry for this variant (Variation ID: 252092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 622 of the LDLR protein (p.Asp622Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. (less)
|
|
|
Likely pathogenic
(Feb 23, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Hypercholesterolemia, familial, 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
biparental,
unknown,
maternal
|
First Hospital of Lanzhou University, Lanzhou University
Accession: SCV004801928.1
First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024 |
Comment:
A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain … (more)
A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery diseaseThe patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, Evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband father, both brothers and daughter carried the c.1448G> A variant. Without exception, all of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family. (less)
Observation 1:
Clinical Features:
Hypercholesterolemia (present) , Xanthelasma (present) , Tendon xanthomatosis (present) , Atherosclerosis (present)
Age: 30-39 years
Sex: female
Ethnicity/Population group: Han nationality
Geographic origin: China
Observation 2:
Clinical Features:
Hypercholesterolemia (present)
Age: 60-69 years
Sex: female
Ethnicity/Population group: Han nationality
Geographic origin: China
Observation 3:
Clinical Features:
Hypercholesterolemia (present)
Age: 40-49 years
Sex: female
Ethnicity/Population group: Han nationality
Geographic origin: China
Observation 4:
Clinical Features:
Hypercholesterolemia (present)
Age: 10-19 years
Sex: male
Ethnicity/Population group: Han nationality
Geographic origin: China
|
Comment:
Comment:
A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery diseaseThe patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, Evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband father, both brothers and daughter carried the c.1448G> A variant. Without exception, all of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family.
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. This variant disrupts the p.Asp662 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15701167, 16159606, 22698793), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Experimental studies have shown that this missense change decreases LDL binding and uptake (PMID: 28645073). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 15701167, 27824480, 28645073, 22698793, Invitae. This variant is also known as p.D601N in the literature. ClinVar contains an entry for this variant (Variation ID: 252092). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 622 of the LDLR protein (p.Asp622Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine.
Comment:
A 38-year-old female proband carried a compliant heterozygous variant (c.292G>A,c.1864G> A and c.1448G> A, according to the ACMG guidelines they were separately classified as Uncertain significance, Likely pathogenic and pathogenic).The proband presented with a xanthoma, corneal aneurysm, and coronary artery diseaseThe patient's serum cholesterol concentration remained greater than 13 mmol/L after receiving intensive statin, Evolocumab and Inclisiran therapy.We speculate that the hepatocytes of the proband indicate the almostly absence of LDLR. The proband's mother, sister, and son all carried the c.292G>A,c.1864G> A variant. The proband father, both brothers and daughter carried the c.1448G> A variant. Without exception, all of her relatives showed hypercholesterolemia, but no atherosclerosis, xanthoma, or corneal aneurysm in the other relatives except the proband. Pedigree co-segregation evidence suggests that the three variants may be pathogenic variants in this familial hypercholesterolemic family.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The molecular genetic background of familial hypercholesterolemia: data from the Slovak nation-wide survey. | Gabčová D | Physiological research | 2017 | PMID: 27824480 |
| The molecular basis of familial hypercholesterolemia in the Czech Republic: spectrum of LDLR mutations and genotype-phenotype correlations. | Tichý L | Atherosclerosis | 2012 | PMID: 22698793 |
| 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 |
Text-mined citations for rs879255059 ...
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 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.