NM_000527.5(LDLR):c.1201C>G (p.Leu401Val) AND Familial hypercholesterolemia

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 11, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000586642.20

Allele description [Variation Report for NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)]

NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)

Gene:

LDLR:low density lipoprotein receptor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)

HGVS:

NC_000019.10:g.11113292C>G
NG_009060.1:g.28912C>G
NM_000527.5:c.1201C>GMANE SELECT
NM_001195798.2:c.1201C>G
NM_001195799.2:c.1078C>G
NM_001195800.2:c.697C>G
NM_001195803.2:c.820C>G
NP_000518.1:p.Leu401Val
NP_000518.1:p.Leu401Val
NP_001182727.1:p.Leu401Val
NP_001182728.1:p.Leu360Val
NP_001182729.1:p.Leu233Val
NP_001182732.1:p.Leu274Val
LRG_274t1:c.1201C>G
LRG_274:g.28912C>G
LRG_274p1:p.Leu401Val
NC_000019.9:g.11223968C>G
NM_000527.4:c.1201C>G
P01130:p.Leu401Val
c.1201C>G

Protein change:

L233V

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000535; UniProtKB: P01130#VAR_007987

Molecular consequence:

NM_000527.5:c.1201C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1201C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1078C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.697C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.820C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
Identifiers:: MONDO: MONDO:0005439; MedGen: C0020445; OMIM: PS143890

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000627015	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9104431, 12124988, 21722902, 24507775, 25461735, 7573037, 11810272, 15701167, 19843101, 28492532
SCV000697189	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 28, 2016)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25637381, 9104431, 25461735, 23833242, 21722902 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001347900	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002086413	Natera, Inc.	no assertion criteria provided	Pathogenic (Jan 22, 2020)	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The UMD-LDLR database: additions to the software and 490 new entries to the database.

Villéger L, Abifadel M, Allard D, Rabès JP, Thiart R, Kotze MJ, Béroud C, Junien C, Boileau C, Varret M.

Hum Mutat. 2002 Aug;20(2):81-7. Review.

PubMed [citation]

PMID:: 12124988

Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

Lange LA, Hu Y, Zhang H, Xue C, Schmidt EM, Tang ZZ, Bizon C, Lange EM, Smith JD, Turner EH, Jun G, Kang HM, Peloso G, Auer P, Li KP, Flannick J, Zhang J, Fuchsberger C, Gaulton K, Lindgren C, Locke A, Manning A, et al.

Am J Hum Genet. 2014 Feb 6;94(2):233-45. doi: 10.1016/j.ajhg.2014.01.010.

PubMed [citation]

PMID:: 24507775
PMCID:: PMC3928660

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000627015.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697189.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Color Diagnostics, LLC DBA Color Health, SCV001347900.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV002086413.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 24, 2024

ClinVar

Relating variation to medicine