VCV000251531.10 - ClinVar

NM_000527.5(LDLR):c.932A>C (p.Lys311Thr)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

6 submitters

3 conditions

Reviewed by expert panel

Uncertain significance

Jan 2022 by ClinGen Famili… FDA Recognized Database

for Hypercholesterolemia, familial, 1

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000527.5(LDLR):c.932A>C (p.Lys311Thr)

Variation ID: 251531 Accession: VCV000251531.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 11107506 (GRCh38) [ NCBI UCSC ] 19: 11218182 (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	Nov 24, 2024	Jan 14, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_000527.5:c.932A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000518.1:p.Lys311Thr	missense
NM_001195798.2:c.932A>C	NP_001182727.1:p.Lys311Thr	missense
NM_001195799.2:c.809A>C	NP_001182728.1:p.Lys270Thr	missense
NM_001195800.2:c.428A>C	NP_001182729.1:p.Lys143Thr	missense
NM_001195803.2:c.551A>C	NP_001182732.1:p.Lys184Thr	missense
NC_000019.10:g.11107506A>C
NC_000019.9:g.11218182A>C
NG_009060.1:g.23126A>C
LRG_274:g.23126A>C
LRG_274t1:c.932A>C

... more HGVS ... less HGVS

Protein change

K311T, K184T, K143T, K270T

Other names

NM_000527.5(LDLR):c.932A>C
p.Lys311Thr

Canonical SPDI

NC_000019.10:11107505:A:C

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.

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

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA10585200 LDLR-LOVD, British Heart Foundation: LDLR_001125 dbSNP: rs761765254 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.
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.
Hypercholesterolemia, familial, 1	Uncertain significance (2)	reviewed by expert panel	Jan 14, 2022	RCV000237873.4
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 25, 2024	RCV002223827.3
Familial hypercholesterolemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Feb 24, 2022	RCV002251448.6

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 (Jan 14, 2022)	reviewed by expert panel (ClinGen FH ACMG Specifications v1-2) Method: curation	Hypercholesterolemia, familial, 1 (Semidominant inheritance) Affected status: unknown Allele origin: germline	ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel FDA Recognized Database Accession: SCV002506363.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4792b635-e961-4626-a094-25b7b23babb6 Comment: The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by … (more) The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.787. It is above 0.75, so PP3 is Met. (less)
Likely pathogenic (Mar 25, 2016)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: literature only	Familial hypercholesterolemia (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	LDLR-LOVD, British Heart Foundation Accession: SCV000295063.2 First in ClinVar: Jul 29, 2016 Last updated: Jul 29, 2016	Publications: PubMed (1) PubMed: 15556094 Number of individuals with the variant: 1
Uncertain significance (Nov 02, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002502938.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (2) PubMed: 15556094‚ 25487149 Number of individuals with the variant: 1 Secondary finding: no
Likely pathogenic (Aug 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial hypercholesterolemia Affected status: yes Allele origin: germline	National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health Accession: SCV002522178.2 First in ClinVar: Jun 05, 2022 Last updated: Oct 07, 2023
Uncertain significance (Feb 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Familial hypercholesterolemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003497507.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (1) PubMed: 15556094 Comment: This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 311 of the LDLR protein (p.Lys311Thr). … (more) This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 311 of the LDLR protein (p.Lys311Thr). This variant is present in population databases (rs761765254, gnomAD 0.007%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15556094). This variant is also known as p.K290T. ClinVar contains an entry for this variant (Variation ID: 251531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
Likely pathogenic (Sep 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005413308.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 15556094‚ 25487149‚ 33418990‚ 35460704 Comment: PP3, PM2, PM3_strong Number of individuals with the variant: 1

Comment:

The NM_000527.5(LDLR):c.932A>C (p.Lys311Thr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2 and PM3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2 - PopMax MAF = 0.00006488 (0.006488%) in European (non-Finnish) genomes (gnomAD v2.1.1), so PM2 is Met. PP3 - REVEL = 0.787. It is above 0.75, so PP3 is Met.

Comment:

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 311 of the LDLR protein (p.Lys311Thr). This variant is present in population databases (rs761765254, gnomAD 0.007%). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 15556094). This variant is also known as p.K290T. ClinVar contains an entry for this variant (Variation ID: 251531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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
Whole-exome sequencing reveals damaging gene variants associated with hypoalphalipoproteinemia.	Dong W	Journal of lipid research	2022	PMID: 35460704
The LDLR, APOB, and PCSK9 Variants of Index Patients with Familial Hypercholesterolemia in Russia.	Meshkov A	Genes	2021	PMID: 33418990
Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.	Do R	Nature	2015	PMID: 25487149
Genetic screening of patients with familial hypercholesterolaemia (FH): a New Zealand perspective.	Laurie AD	Atherosclerosis. Supplements	2004	PMID: 15556094
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4792b635-e961-4626-a094-25b7b23babb6	-	-	-	-

Text-mined citations for rs761765254 ...

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_000527.5(LDLR):c.932A>C (p.Lys311Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs761765254 ...