NM_000527.5(LDLR):c.1883T>C (p.Ile628Thr) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Apr 6, 2021
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:: RCV001857832.6

Allele description [Variation Report for NM_000527.5(LDLR):c.1883T>C (p.Ile628Thr)]

NM_000527.5(LDLR):c.1883T>C (p.Ile628Thr)

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.1883T>C (p.Ile628Thr)

HGVS:

NC_000019.10:g.11120129T>C
NG_009060.1:g.35749T>C
NM_000527.5:c.1883T>CMANE SELECT
NM_001195798.2:c.1883T>C
NM_001195799.2:c.1760T>C
NM_001195800.2:c.1379T>C
NM_001195803.2:c.1502T>C
NP_000518.1:p.Ile628Thr
NP_001182727.1:p.Ile628Thr
NP_001182728.1:p.Ile587Thr
NP_001182729.1:p.Ile460Thr
NP_001182732.1:p.Ile501Thr
LRG_274t1:c.1883T>C
LRG_274:g.35749T>C
NC_000019.9:g.11230805T>C
NM_000527.4:c.1883T>C
c.1883T>C

Protein change:

I460T

Links:

LDLR-LOVD, British Heart Foundation: LDLR_001539; dbSNP: rs879255067

NCBI 1000 Genomes Browser:

rs879255067

Molecular consequence:

NM_000527.5:c.1883T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1883T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1760T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1379T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1502T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypercholesterolemia
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
SCV002185875	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 6, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15199436, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002185875

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 6, 2021)

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

Application of molecular genetics for diagnosing familial hypercholesterolemia in Norway: results from a family-based screening program.

Leren TP, Manshaus T, Skovholt U, Skodje T, Nossen IE, Teie C, Sørensen S, Bakken KS.

Semin Vasc Med. 2004 Feb;4(1):75-85. Review.

PubMed [citation]

PMID:: 15199436

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002185875.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with Familial hypercholesterolemia (PMID: 15199436). ClinVar contains an entry for this variant (Variation ID: 252103). This variant is also described as I607T in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 628 of the LDLR protein (p.Ile628Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine.

#	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 29, 2024

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