NM_000527.5(LDLR):c.2311G>A (p.Ala771Thr) AND Familial hypercholesterolemia

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 15, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001856995.6

Allele description [Variation Report for NM_000527.5(LDLR):c.2311G>A (p.Ala771Thr)]

NM_000527.5(LDLR):c.2311G>A (p.Ala771Thr)

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.2311G>A (p.Ala771Thr)

HGVS:

NC_000019.10:g.11123344G>A
NG_009060.1:g.38964G>A
NM_000527.5:c.2311G>AMANE SELECT
NM_001195798.2:c.2311G>A
NM_001195799.2:c.2188G>A
NM_001195800.2:c.1807G>A
NM_001195803.2:c.1777G>A
NP_000518.1:p.Ala771Thr
NP_000518.1:p.Ala771Thr
NP_001182727.1:p.Ala771Thr
NP_001182728.1:p.Ala730Thr
NP_001182729.1:p.Ala603Thr
NP_001182732.1:p.Ala593Thr
LRG_274t1:c.2311G>A
LRG_274:g.38964G>A
LRG_274p1:p.Ala771Thr
NC_000019.9:g.11234020G>A
NM_000527.4:c.2311G>A

Protein change:

A593T

Links:

Molecular consequence:

NM_000527.5:c.2311G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195798.2:c.2311G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195799.2:c.2188G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195800.2:c.1807G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001195803.2:c.1777G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

Recent activity

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Homo sapiens BRCA2 DNA repair associated (BRCA2), transcript variant 1, mRNA
Homo sapiens BRCA2 DNA repair associated (BRCA2), transcript variant 1, mRNA
gi|1813836564|ref|NM_000059.4|

Nucleotide
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002200678	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 1, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26802169, 17576681, 9536098, 28492532
SCV004359068	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Apr 5, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26802169, 25741868
SCV005076167	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Apr 15, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26802169, 37813054 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002200678

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 1, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004359068

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Apr 5, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005076167

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Apr 15, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002200678.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 771 of the LDLR protein (p.Ala771Thr). This variant also falls at the last nucleotide of exon 15, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 26802169). ClinVar contains an entry for this variant (Variation ID: 431545). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, SCV004359068.1

#	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.Ala750Thr in the mature protein) replaces alanine with threonine at codon 771 of the LDLR protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). However, this variant causes a G>A nucleotide substitution at the last nucleotide of exon 15 of the LDLR gene, and splice site prediction tools suggest that this variant may have significant impact on the RNA splicing. A mini-gene splicing assay has shown that this variant causes complete abolition of the natural splice site and exclusive use of two cryptic splice sites at c.2311+90 and at c.2190 (PMID: 26802169). This variant has been reported in an individual affected with hypercholesterolemia (PMID: 26802169). This variant has not been identified 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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005076167.1

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

Description

Variant summary: LDLR c.2311G>A (p.Ala771Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a canonical 5' donor site and one predicts the variant abolishes this site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Wintjens_2016). The variant was absent in 250596 control chromosomes (gnomAD). c.2311G>A has been reported in the literature in individuals affected with Familial Hypercholesterolemia (e.g. Wintjens_2016, Albuquerque_2023). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26802169, 37813054). ClinVar contains an entry for this variant (Variation ID: 431545). Based on the evidence outlined above, the variant was classified as likely 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: Sep 29, 2024

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