NM_000527.5(LDLR):c.673_675inv (p.Lys225Phe) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 12, 2022
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:: RCV003043620.2

Allele description [Variation Report for NM_000527.5(LDLR):c.673_675inv (p.Lys225Phe)]

NM_000527.5(LDLR):c.673_675inv (p.Lys225Phe)

Gene:

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

Variant type:

Inversion

Cytogenetic location:

19p13.2

Genomic location:

Preferred name:

NM_000527.5(LDLR):c.673_675inv (p.Lys225Phe)

HGVS:

NC_000019.10:g.11105579_11105581inv
NG_009060.1:g.21199_21201inv
NM_000527.5:c.673_675invMANE SELECT
NM_001195798.2:c.673_675inv
NM_001195799.2:c.550_552inv
NM_001195800.2:c.314-1813_314-1811inv
NM_001195803.2:c.314-986_314-984inv
NP_000518.1:p.Lys225Phe
NP_000518.1:p.Lys225Phe
NP_001182727.1:p.Lys225Phe
NP_001182728.1:p.Lys184Phe
LRG_274t1:c.673_675invAAA
LRG_274:g.21199_21201inv
LRG_274p1:p.Lys225Phe
NC_000019.9:g.11216255_11216257delinsTTT
NC_000019.9:g.11216255_11216257inv
NM_000527.4:c.673_675invAAA

Protein change:

K184F

Molecular consequence:

NM_001195800.2:c.314-1813_314-1811inv - intron variant - [Sequence Ontology: SO:0001627]
NM_001195803.2:c.314-986_314-984inv - intron variant - [Sequence Ontology: SO:0001627]
NM_000527.5:c.673_675inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.673_675inv - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.550_552inv - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003345315	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 12, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003345315

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 12, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV003345315.2

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

Description

This sequence change replaces lysine, which is basic and polar, with phenylalanine, which is neutral and non-polar, at codon 225 of the LDLR protein (p.Lys225Phe). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with LDLR-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Feb 20, 2024

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