NM_000527.5(LDLR):c.1201C>G (p.Leu401Val) AND not provided

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: May 24, 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:: RCV000255176.13

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000322301	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (May 24, 2024)	germline	clinical testing	Citation Link,
SCV002502785	AiLife Diagnostics, AiLife Diagnostics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 2, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 9104431, 25637381, 32041611, 30586733, 24507775, 33740630, 34037665, 31447099, 25741868
SCV004219938	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Likely pathogenic (Aug 10, 2022)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 33740630, 34037665, 9104431, 32041611, 25461735, 23833242, 21722902, 32715071, 10090473, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000322301

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(May 24, 2024)

germline

clinical testing

Citation Link,

SCV002502785

AiLife Diagnostics, AiLife Diagnostics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 2, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

SCV004219938

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Likely pathogenic
(Aug 10, 2022)

unknown

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, et al.

Genome Res. 2015 Mar;25(3):305-15. doi: 10.1101/gr.183483.114. Epub 2015 Jan 30.

PubMed [citation]

PMID:: 25637381
PMCID:: PMC4352885

Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.

Khera AV, Chaffin M, Zekavat SM, Collins RL, Roselli C, Natarajan P, Lichtman JH, D'Onofrio G, Mattera J, Dreyer R, Spertus JA, Taylor KD, Psaty BM, Rich SS, Post W, Gupta N, Gabriel S, Lander E, Ida Chen YD, Talkowski ME, Rotter JI, Krumholz HM, et al.

Circulation. 2019 Mar 26;139(13):1593-1602. doi: 10.1161/CIRCULATIONAHA.118.035658.

PubMed [citation]

PMID:: 30586733
PMCID:: PMC6433484

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000322301.11

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

Description

Reported in individuals with a history of early-onset myocardial infarction (PMID: 30586733); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(L380V); This variant is associated with the following publications: (PMID: 12124988, 25461735, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34037665, 34040191, 33955087, 22683370, 21957200, 9104431, 30586733)

#	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 AiLife Diagnostics, AiLife Diagnostics, SCV002502785.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (9)

#	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		1	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004219938.1

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

Description

The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021) and 33740630 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.

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

Last Updated: Nov 3, 2024

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