NM_000527.5(LDLR):c.1322T>G (p.Ile441Ser) AND Cardiovascular phenotype

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 27, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV004518663.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1322T>G (p.Ile441Ser)]

NM_000527.5(LDLR):c.1322T>G (p.Ile441Ser)

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.1322T>G (p.Ile441Ser)

HGVS:

NC_000019.10:g.11113413T>G
NG_009060.1:g.29033T>G
NM_000527.5:c.1322T>GMANE SELECT
NM_001195798.2:c.1322T>G
NM_001195799.2:c.1199T>G
NM_001195800.2:c.818T>G
NM_001195803.2:c.941T>G
NP_000518.1:p.Ile441Ser
NP_000518.1:p.Ile441Ser
NP_001182727.1:p.Ile441Ser
NP_001182728.1:p.Ile400Ser
NP_001182729.1:p.Ile273Ser
NP_001182732.1:p.Ile314Ser
LRG_274t1:c.1322T>G
LRG_274:g.29033T>G
LRG_274p1:p.Ile441Ser
NC_000019.9:g.11224089T>G
NM_000527.4:c.1322T>G

Protein change:

I273S

Molecular consequence:

NM_000527.5:c.1322T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1322T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1199T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.818T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.941T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cardiovascular phenotype
Identifiers:: MedGen: CN230736

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005035874	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Feb 27, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005035874

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Feb 27, 2024)

germline

clinical testing

Citation Link

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

Details of each submission

From Ambry Genetics, SCV005035874.1

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

Description

The p.I441S variant (also known as c.1322T>G), located in coding exon 9 of the LDLR gene, results from a T to G substitution at nucleotide position 1322. The isoleucine at codon 441 is replaced by serine, an amino acid with dissimilar properties. This variant has been observed in at least one individual with a personal and/or family history that is consistent with familial hypercholesterolemia (FH) (Ambry internal data). Another alteration at the same codon, p.I441T (c.1322T>C), has been described in multiple individuals with FH (Fouchier SW et al. Hum. Genet., 2001 Dec;109:602-15; Medeiros AM et al. Atherosclerosis, 2010 Oct;212:553-8; Chiu CY et al. Metab. Clin. Exp., 2005 Aug;54:1082-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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

Last Updated: May 7, 2024

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