NM_000527.5(LDLR):c.1323C>G (p.Ile441Met) AND Homozygous familial hypercholesterolemia

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: May 4, 2018
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:: RCV004017555.1

Allele description [Variation Report for NM_000527.5(LDLR):c.1323C>G (p.Ile441Met)]

NM_000527.5(LDLR):c.1323C>G (p.Ile441Met)

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.1323C>G (p.Ile441Met)

Other names:

FH Roen; NM_000527.5(LDLR):c.1323C>G

HGVS:

NC_000019.10:g.11113414C>G
NG_009060.1:g.29034C>G
NM_000527.5:c.1323C>GMANE SELECT
NM_001195798.2:c.1323C>G
NM_001195799.2:c.1200C>G
NM_001195800.2:c.819C>G
NM_001195803.2:c.942C>G
NP_000518.1:p.Ile441Met
NP_000518.1:p.Ile441Met
NP_001182727.1:p.Ile441Met
NP_001182728.1:p.Ile400Met
NP_001182729.1:p.Ile273Met
NP_001182732.1:p.Ile314Met
LRG_274t1:c.1323C>G
LRG_274:g.29034C>G
LRG_274p1:p.Ile441Met
NC_000019.9:g.11224090C>G
NM_000527.4:c.1323C>G
P01130:p.Ile441Met
c.1323C>G

Protein change:

I273M

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001397; UniProtKB: P01130#VAR_005388; dbSNP: rs5933

NCBI 1000 Genomes Browser:

rs5933

Molecular consequence:

NM_000527.5:c.1323C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1323C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1200C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.819C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.942C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Homozygous familial hypercholesterolemia
Synonyms:: Familial hypercholesterolemia - homozygous
Identifiers:: MONDO: MONDO:0018328; MedGen: C0342881

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004848208	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (May 4, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 1301956, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004848208

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely Pathogenic
(May 4, 2018)

germline

clinical testing

PubMed (2)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular genetics of the LDL receptor gene in familial hypercholesterolemia.

Hobbs HH, Brown MS, Goldstein JL.

Hum Mutat. 1992;1(6):445-66. Review.

PubMed [citation]

PMID:: 1301956

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848208.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Ile441Met variant (reported as p.Ile420Met) in LDLR has been reported in 1 individual with hypercholesterolemia (Hobbs 1992). This variant is also reported in ClinVar (Variation ID: 251784), and was absent from large population studies. In vitro functional studies using fibroblasts derived from skin cells of the patient with this variant exhibit a significant impact on LDLR receptor activity (Hobbs 1992). In addition, computational prediction tools and conservation analysis suggest that the p.Ile441Met variant may impact the protein. Furthermore, two other variants at the same amino acid position (p.Ile441Asn and p.Ile441Thr) were identified in several patients with hypercholesterolemia and segregated in affected family members, and in vitro functional studies of both variants reveal an impact to receptor function (Benito-Vicente and Hobbs 1992). This data supports a causative role for the p.Ile441Met variant and suggests that changes at this amino acid position are not tolerated. In summary, although additional studies are required to fully establish its clinical significance, the p.Ile441Met variant is likely pathogenic. ACMG/AMP Criteria applied: PM5_Strong, PM2, PP3, PS3_Supporting.

#	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: Sep 1, 2024

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