BS1_Strong,BP4
NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)
Germline
Classification
Help
criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.
Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2); Benign(1); Likely benign(4)
Likely pathogenic(1); Uncertain significance(2); Benign(1); Likely benign(4)
8 out of 10 submissions contributed to this 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.
10
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)
Variation ID: 4776 Accession: VCV000004776.20
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p36.11 1: 25563142 (GRCh38) [ NCBI UCSC ] 1: 25889633 (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 Mar 17, 2018 Apr 25, 2026 Mar 27, 2026 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_015627.3:c.605C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_056442.2:p.Ser202Tyr missense NC_000001.11:g.25563142C>A NC_000001.10:g.25889633C>A NG_008932.1:g.24558C>A LRG_276:g.24558C>A LRG_276t1:c.605C>A LRG_276p1:p.Ser202Tyr - Protein change
- S202Y
- Other names
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P202H
- Canonical SPDI
- NC_000001.11:25563141:C:A
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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.
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0.00160 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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1000 Genomes Project 30x 0.00141
Trans-Omics for Precision Medicine (TOPMed) 0.00186
The Genome Aggregation Database (gnomAD) 0.00147
1000 Genomes Project 0.00160
- 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. |
|||
| LDLRAP1 | - | - |
GRCh38 GRCh37 |
576 | 693 | |
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. |
|---|---|---|---|---|
| Conflicting classifications of pathogenicity (5) |
criteria provided, conflicting classifications
|
Aug 25, 2021 | RCV000005042.22 | |
| Likely benign (2) |
criteria provided, single submitter
|
Aug 6, 2025 | RCV001275174.2 | |
| Conflicting classifications of pathogenicity (2) |
criteria provided, conflicting classifications
|
Mar 27, 2026 | RCV004585986.2 | |
| Likely benign (1) |
criteria provided, single submitter
|
Nov 1, 2025 | RCV006434909.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
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 benign
(Dec 31, 2019)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolemia 4 |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001031361.2
First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Aug 06, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Familial hypercholesterolaemia |
Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service
Accession: SCV007131332.1
First in ClinVar: Jan 11, 2026 Last updated: Jan 11, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Benign
(Jul 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 4 |
Illumina Laboratory Services, Illumina
Accession: SCV001259183.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
show
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Likely pathogenic
(May 24, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 4 |
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II
Accession: SCV001653675.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
show
Identified at heterozygous status in a patient with clinical suspect of Familial Hypercholesterolemia without pathogenic variants in LDLR, APOB, PCSK9, APOE, STAP1, ABCG5, ABCG8, LIPA and other lipid-related genes by next-generation sequencing. Likely pathogenic if in trans with an additional LDLRAP1 variant; probably affecting cholesterol levels at heterozygous status. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
Ethnicity/Population group: Caucasian
Geographic origin: Italy
|
|
|
Uncertain significance
(Apr 16, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000699408.2
First in ClinVar: Mar 17, 2018 Last updated: Jul 15, 2024 |
Comment:
show
Variant summary: LDLRAP1 c.605C>A (p.Ser202Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 1613942 control chromosomes in the gnomAD database, including 6 homozygotes. c.605C>A has been reported in the literature in multiple heterozygous individuals affected with or with clinical features of Familial Hypercholesterolemia, without strong evidence for causality, with frequent reporting as a VUS (e.g. Rubba_2017, Luirink_2019, Rieck_2020, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25911074, 11326085, 30795984, 32770674, 35047021, 28353356). ClinVar contains an entry for this variant (Variation ID: 4776). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Uncertain significance
(Aug 25, 2021)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hypercholesterolemia, familial, 4 |
Department of Pathology and Laboratory Medicine, Sinai Health System
Accession: SCV006057246.1
First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025 |
Observation: 1
Collection method: research
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: research
Allele origin: germline
Affected status: unknown
|
|
|
Likely benign
(Mar 27, 2026)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not specified |
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute
Accession: SCV000987666.2
First in ClinVar: Sep 08, 2019 Last updated: Apr 25, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: no
|
|
|
Likely benign
(Nov 01, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
CeGaT Center for Human Genetics Tuebingen
Accession: SCV007295193.2
First in ClinVar: Jan 11, 2026 Last updated: Apr 25, 2026 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(May 18, 2001)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE
|
OMIM
Accession: SCV000025218.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2019 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
In a Lebanese family (ARH4) with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) found that all affected individuals were homozygous for a C-to-A … (more)
In a Lebanese family (ARH4) with autosomal recessive hypercholesterolemia (FHCL4; 603813), Garcia et al. (2001) found that all affected individuals were homozygous for a C-to-A transversion at nucleotide 605 of the ARH gene, resulting in a pro-to-his substitution at codon 202 (P202H). Family members had plasma total cholesterol of 520 to 610 mg/dl, with LDL cholesterol ranging from 392 to 520 dl. (less)
|
|
|
Uncertain significance
(Jan 11, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Familial hypercholesterolemia |
Natera, Inc.
Accession: SCV001460019.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
Comment:
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Comment:
Identified at heterozygous status in a patient with clinical suspect of Familial Hypercholesterolemia without pathogenic variants in LDLR, APOB, PCSK9, APOE, STAP1, ABCG5, ABCG8, LIPA and other lipid-related genes by next-generation sequencing. Likely pathogenic if in trans with an additional LDLRAP1 variant; probably affecting cholesterol levels at heterozygous status.
Comment:
Variant summary: LDLRAP1 c.605C>A (p.Ser202Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00084 in 1613942 control chromosomes in the gnomAD database, including 6 homozygotes. c.605C>A has been reported in the literature in multiple heterozygous individuals affected with or with clinical features of Familial Hypercholesterolemia, without strong evidence for causality, with frequent reporting as a VUS (e.g. Rubba_2017, Luirink_2019, Rieck_2020, Rimbert_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25911074, 11326085, 30795984, 32770674, 35047021, 28353356). ClinVar contains an entry for this variant (Variation ID: 4776). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Comment:
BS1, BP1, BP4
Comment:
LDLRAP1: BP4, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Low Detection Rates of Genetic FH in Cohort of Patients With Severe Hypercholesterolemia in the United Arabic Emirates. | Rimbert A | Frontiers in genetics | 2022 | PMID: 35047021 |
| Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia. | Rieck L | Clinical genetics | 2020 | PMID: 32770674 |
| The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA) study. | Luirink IK | Journal of clinical lipidology | 2019 | PMID: 30795984 |
| Spectrum of mutations in Italian patients with familial hypercholesterolemia: New results from the LIPIGEN study. | Pirillo A | Atherosclerosis. Supplements | 2017 | PMID: 28965616 |
| Causative mutations and premature cardiovascular disease in patients with heterozygous familial hypercholesterolaemia. | Rubba P | European journal of preventive cardiology | 2017 | PMID: 28353356 |
| Familial hypercholesterolemia mutations in the Middle Eastern and North African region: a need for a national registry. | Bamimore MA | Journal of clinical lipidology | 2015 | PMID: 25911074 |
| Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. | Garcia CK | Science (New York, N.Y.) | 2001 | PMID: 11326085 |
Text-mined citations for rs121908326 ...
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 Apr 26, 2026
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.