VCV000004776.17 - ClinVar

NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)

Germline

Classification

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.

(7)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

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: VCV000004776.17

Type and length

single nucleotide variant, 1 bp

Location

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	Jul 15, 2024	Apr 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

S202Y

Other names

P202H

Canonical SPDI

NC_000001.11:25563141:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00160 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00141

The Genome Aggregation Database (gnomAD) 0.00147

1000 Genomes Project 0.00160

Trans-Omics for Precision Medicine (TOPMed) 0.00186

Links

ClinGen: CA117073 OMIM: 605747.0004 dbSNP: rs121908326 VarSome

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
Gene	OMIM	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	483	575

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.
Hypercholesterolemia, familial, 4	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	May 24, 2021	RCV000005042.19
Familial hypercholesterolemia	Uncertain significance (1)	no assertion criteria provided	Jan 11, 2020	RCV001275174.1
not specified	Uncertain significance (1)	criteria provided, single submitter	Apr 16, 2024	RCV004585986.1

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.
Uncertain significance (Apr 16, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000699408.2 First in ClinVar: Mar 17, 2018 Last updated: Jul 15, 2024	Publications: PubMed (6) PubMed: 25911074‚ 11326085‚ 30795984‚ 28353356‚ 32770674‚ 35047021 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 … (more) 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)
Uncertain significance (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 4 Affected status: yes Allele origin: germline	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute Accession: SCV000987666.1 First in ClinVar: Sep 08, 2019 Last updated: Sep 08, 2019
Likely benign (Dec 31, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001031361.2 First in ClinVar: Dec 17, 2019 Last updated: May 04, 2020
Benign (Jul 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Hypercholesterolemia, familial, 4 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001259183.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 11326085‚ 25911074 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, … (more) 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)
Likely pathogenic (May 24, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypercholesterolemia, familial, 4 Affected status: yes Allele origin: germline	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	Publications: PubMed (2) PubMed: 28353356‚ 28965616 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 … (more) 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) Number of individuals with the variant: 1 Ethnicity/Population group: Caucasian Geographic origin: Italy
Pathogenic (May 18, 2001)	no assertion criteria provided Method: literature only	HYPERCHOLESTEROLEMIA, FAMILIAL, 4, AUTOSOMAL RECESSIVE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025218.3 First in ClinVar: Apr 04, 2013 Last updated: Jun 22, 2019	Publications: PubMed (1) PubMed: 11326085 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)	no assertion criteria provided Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460019.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

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:

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.

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:

Citations for germline classification of this variant

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 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_015627.3(LDLRAP1):c.605C>A (p.Ser202Tyr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121908326 ...