NM_000527.5(LDLR):c.148G>T (p.Ala50Ser) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 4, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000455660.20

Allele description [Variation Report for NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)]

NM_000527.5(LDLR):c.148G>T (p.Ala50Ser)

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.148G>T (p.Ala50Ser)

Other names:

NP_000518.1:p.A50S

HGVS:

NC_000019.10:g.11100303G>T
NG_009060.1:g.15923G>T
NM_000527.5:c.148G>TMANE SELECT
NM_001195798.2:c.148G>T
NM_001195799.2:c.148G>T
NM_001195800.2:c.148G>T
NM_001195803.2:c.148G>T
NP_000518.1:p.Ala50Ser
NP_000518.1:p.Ala50Ser
NP_001182727.1:p.Ala50Ser
NP_001182728.1:p.Ala50Ser
NP_001182729.1:p.Ala50Ser
NP_001182732.1:p.Ala50Ser
LRG_274t1:c.148G>T
LRG_274:g.15923G>T
LRG_274p1:p.Ala50Ser
NC_000019.9:g.11210979G>T
NM_000527.4:c.148G>T
P01130:p.Ala50Ser
c.148G>T

Protein change:

A50S

Links:

LDLR-LOVD, British Heart Foundation: LDLR_000021; UniProtKB: P01130#VAR_007979; dbSNP: rs137853960

NCBI 1000 Genomes Browser:

rs137853960

Molecular consequence:

NM_000527.5:c.148G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.148G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.148G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.148G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.148G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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Homo sapiens nuclear receptor subfamily 0 group B member 2 (NR0B2), mRNA
Homo sapiens nuclear receptor subfamily 0 group B member 2 (NR0B2), mRNA
gi|1519241638|ref|NM_021969.3|

Nucleotide
Mus musculus pancreatic lipase (Pnlip), mRNA
Mus musculus pancreatic lipase (Pnlip), mRNA
gi|1433354059|ref|NM_026925.4|

Nucleotide
HPODL_01798 [Ogataea parapolymorpha DL-1]
HPODL_01798 [Ogataea parapolymorpha DL-1]
Gene ID:25771255

Gene
HPODL_01643 [Ogataea parapolymorpha DL-1]
HPODL_01643 [Ogataea parapolymorpha DL-1]
Gene ID:25771102

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000539514	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Mar 31, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000919594	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Dec 4, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 15823280, 16542394, 7820934, 15199436, 10735632, 11810272, 20145306, 20428891, 23064986, 24055113, 24956927, 19717150, 22923420, 24507775, 25487149, 28145427, 10090484, 30333156, 35913489 Citation Link,
SCV001922567	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV001966630	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing

Help

Summary from all submissions

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

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study.

Koeijvoets KC, Wiegman A, Rodenburg J, Defesche JC, Kastelein JJ, Sijbrands EJ.

Atherosclerosis. 2005 May;180(1):93-9. Epub 2004 Dec 19.

PubMed [citation]

PMID:: 15823280

See all PubMed Citations (20)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539514.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 5 papers describe as VUS/nonpathogenic; ExAC: 0.1% (67/66532) European; ClinVar: 1 VUS

#	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, SCV000919594.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

Variant summary: LDLR c.148G>T (p.Ala50Ser; also known as p.Ala29Ser) results in a conservative amino acid change located in the first class A repeat domain (IPR002172) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00054 in 262944 control chromosomes, predominantly at a frequency of 0.00097 within the Non-Finnish European subpopulation in the gnomAD database. However, in certain European regions the variant was found with a higher allele frequency, e.g. in the Swedish (0.0018), which is higher than estimated maximum expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (0.0013), suggesting that the variant might be benign. The variant, c.148G>T, has been reported in the literature in individuals affected with hypercholesterolemia, however it was also found in controls and individuals with low LDL cholesterol (Ahmad_2012, Beaudoin_2012, Brusgaard_2006, Chmarra_2010, Do_2015, Ebhardt_1999, Fouchier_2001, Jensen_1994, Junyent_2010, Koeijvoets_2005, Lange_2014, Leren_2004, Tejedor_2010, Geller_2018, Sustar_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. In a family the variant was found to not segregate with disease (Jensen_1994). In addition, co-occurrences with other pathogenic variants have been reported (e.g. LDLR c.12G>A (p.Trp4X); Tejedor_2010 and LDLR c.1033C>T (p.Gln345X) in an internal LCA sample), providing supporting evidence for a benign role. 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: 23064986, 22923420, 16542394, 20145306, 25487149, 24055113, 10090484, 11810272, 30333156, 7820934, 19717150, 15823280, 24507775, 15199436, 10735632, 24956927, 28145427, 20428891, 35913489). 16 other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=12) or VUS (n=4). Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001922567.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001966630.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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