NM_000039.3(APOA1):c.284T>A (p.Phe95Tyr) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 4, 2024
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:: RCV001859797.4

Allele description [Variation Report for NM_000039.3(APOA1):c.284T>A (p.Phe95Tyr)]

NM_000039.3(APOA1):c.284T>A (p.Phe95Tyr)

Genes:

APOA1-AS:APOA1 antisense RNA [Gene - OMIM - HGNC]
APOA1:apolipoprotein A1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q23.3

Genomic location:

Preferred name:

NM_000039.3(APOA1):c.284T>A (p.Phe95Tyr)

HGVS:

NC_000011.10:g.116836328A>T
NG_012021.1:g.6295T>A
NM_000039.3:c.284T>AMANE SELECT
NM_001318017.2:c.284T>A
NM_001318018.2:c.284T>A
NM_001318021.2:c.-44T>A
NP_000030.1:p.Phe95Tyr
NP_000030.1:p.Phe95Tyr
NP_000030.1:p.Phe95Tyr
NP_001304946.1:p.Phe95Tyr
NP_001304947.1:p.Phe95Tyr
LRG_767t1:c.284T>A
LRG_767:g.6295T>A
LRG_767p1:p.Phe95Tyr
NC_000011.9:g.116707044A>T
NM_000039.1:c.284T>A
NM_000039.2:c.284T>A
NM_001318021.1:c.-44T>A

Protein change:

F95Y

Links:

dbSNP: rs138407155

NCBI 1000 Genomes Browser:

rs138407155

Molecular consequence:

NM_000039.3:c.284T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318017.2:c.284T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001318018.2:c.284T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002292367	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 4, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21820994, 24081495, 30184436, 28492532
SCV005325126	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 4, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002292367

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 4, 2024)

germline

clinical testing

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

SCV005325126

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Mar 4, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I.

Rowczenio D, Dogan A, Theis JD, Vrana JA, Lachmann HJ, Wechalekar AD, Gilbertson JA, Hunt T, Gibbs SD, Sattianayagam PT, Pinney JH, Hawkins PN, Gillmore JD.

Am J Pathol. 2011 Oct;179(4):1978-87. doi: 10.1016/j.ajpath.2011.06.024. Epub 2011 Aug 5.

PubMed [citation]

PMID:: 21820994
PMCID:: PMC3181365

Genetic polymorphisms in the APOA1 gene and their relationship with serum HDL cholesterol levels.

Bandarian F, Hedayati M, Daneshpour MS, Naseri M, Azizi F.

Lipids. 2013 Dec;48(12):1207-16. doi: 10.1007/s11745-013-3847-6. Epub 2013 Oct 1.

PubMed [citation]

PMID:: 24081495

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002292367.3

#	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 phenylalanine, which is neutral and non-polar, with tyrosine, which is neutral and polar, at codon 95 of the APOA1 protein (p.Phe95Tyr). This variant is present in population databases (rs138407155, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with amyloidosis or low HDL-cholesterol (PMID: 21820994, 24081495). This variant is also known as Phe71Tyr. ClinVar contains an entry for this variant (Variation ID: 302506). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt APOA1 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on APOA1 function (PMID: 30184436). 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 GeneDx, SCV005325126.1

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

Description

Functional studies show this variant may lead to changes in protein conformation and stability but less so than other known APOA1 variants (PMID: 30184436, 26562506); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as F71Y; This variant is associated with the following publications: (PMID: 26562506, 23806608, 23209431, 34426522, 24081495, 30184436, 21820994, 32041611, 38112957, 30476936)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 8, 2024

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