NM_000527.5(LDLR):c.2388C>T (p.Ile796=) AND not specified

Germline classification:: Likely benign (2 submissions)
Last evaluated:: Jan 14, 2022
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:: RCV000780381.2

Allele description [Variation Report for NM_000527.5(LDLR):c.2388C>T (p.Ile796=)]

NM_000527.5(LDLR):c.2388C>T (p.Ile796=)

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.2388C>T (p.Ile796=)

HGVS:

NC_000019.10:g.11128084C>T
NG_009060.1:g.43704C>T
NM_000527.5:c.2388C>TMANE SELECT
NM_001195798.2:c.2388C>T
NM_001195799.2:c.2265C>T
NM_001195800.2:c.1884C>T
NM_001195803.2:c.1854C>T
NP_000518.1:p.Ile796=
NP_000518.1:p.Ile796=
NP_001182727.1:p.Ile796=
NP_001182728.1:p.Ile755=
NP_001182729.1:p.Ile628=
NP_001182732.1:p.Ile618=
LRG_274t1:c.2388C>T
LRG_274:g.43704C>T
LRG_274p1:p.Ile796=
NC_000019.9:g.11238760C>T
NM_000527.4:c.2388C>T

Links:

dbSNP: rs543852919

NCBI 1000 Genomes Browser:

rs543852919

Molecular consequence:

NM_000527.5:c.2388C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195798.2:c.2388C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195799.2:c.2265C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195800.2:c.1884C>T - synonymous variant - [Sequence Ontology: SO:0001819]
NM_001195803.2:c.1854C>T - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000917584	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Aug 20, 2018)	germline	clinical testing	Citation Link,
SCV002073470	Phosphorus, Inc.	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Jan 14, 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

SCV000917584

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Aug 20, 2018)

germline

clinical testing

Citation Link,

SCV002073470

Phosphorus, Inc.

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Jan 14, 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

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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917584.1

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

Description

Variant summary: LDLR c.2388C>T (p.Ile796Ile) alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 277170 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2388C>T in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variant(s) have been reported in our internal database (LDLR c.1118_1121dupGTGG, p.Tyr375fsX7), providing supporting evidence for a benign role. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "likely benign" and "uncertain significance." Based on the evidence outlined above, the variant was classified as likely benign.

#	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 Phosphorus, Inc., SCV002073470.1

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

Description

This synonymous variant has occurred in GnomAD with a total MAF of 0.0028% and with the highest MAF of 0.0054% in the European population. This position is 2 bp away from a canonical splicing site, and it is not conserved. In silico splicing algorithm predicted no impact on splicing, but no functional studies were performed to confirm this prediction. This variant NM_000527.5(LDLR):c.2388C>T (p.Ile796=) is present in the ClinVar database (ID: 406165). The variant has not occurred in the literature in association with the disease. Considering that the variant has a relatively high frequency in a subpopulation, it has been classified as Likely Benign.

#	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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