NM_000527.5(LDLR):c.1817C>A (p.Ala606Asp) AND Familial hypercholesterolemia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 3, 2023
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:: RCV001865664.7

Allele description [Variation Report for NM_000527.5(LDLR):c.1817C>A (p.Ala606Asp)]

NM_000527.5(LDLR):c.1817C>A (p.Ala606Asp)

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.1817C>A (p.Ala606Asp)

Other names:

NM_000527.5(LDLR):c.1817C>A; p.Ala606Asp

HGVS:

NC_000019.10:g.11116970C>A
NG_009060.1:g.32590C>A
NM_000527.5:c.1817C>AMANE SELECT
NM_001195798.2:c.1817C>A
NM_001195799.2:c.1694C>A
NM_001195800.2:c.1313C>A
NM_001195803.2:c.1436C>A
NP_000518.1:p.Ala606Asp
NP_000518.1:p.Ala606Asp
NP_001182727.1:p.Ala606Asp
NP_001182728.1:p.Ala565Asp
NP_001182729.1:p.Ala438Asp
NP_001182732.1:p.Ala479Asp
LRG_274t1:c.1817C>A
LRG_274:g.32590C>A
LRG_274p1:p.Ala606Asp
NC_000019.9:g.11227646C>A
NM_000527.4:c.1817C>A

Protein change:

A438D

Links:

dbSNP: rs1410295777

NCBI 1000 Genomes Browser:

rs1410295777

Molecular consequence:

NM_000527.5:c.1817C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.1817C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.1694C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1313C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1436C>A - 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
SCV002221135	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004359043	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 3, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17094996, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002221135

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 17, 2021)

germline

clinical testing

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

SCV004359043

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 3, 2023)

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

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

Genetic defects causing familial hypercholesterolaemia: identification of deletions and duplications in the LDL-receptor gene and summary of all mutations found in patients attending the Hammersmith Hospital Lipid Clinic.

Tosi I, Toledo-Leiva P, Neuwirth C, Naoumova RP, Soutar AK.

Atherosclerosis. 2007 Sep;194(1):102-11. Epub 2006 Nov 13.

PubMed [citation]

PMID:: 17094996

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002221135.2

#	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 alanine with aspartic acid at codon 606 of the LDLR protein (p.Ala606Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with LDLR-related conditions. ClinVar contains an entry for this variant (Variation ID: 440663). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

From Color Diagnostics, LLC DBA Color Health, SCV004359043.1

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

Description

This missense variant (also known as p.Ala585Asp in the mature protein) replaces alanine with aspartic acid at codon 606 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17094996). This variant has been identified in 3/251478 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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: Sep 29, 2024

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