NM_006329.4(FBLN5):c.1093A>G (p.Ile365Val) AND not provided

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Nov 24, 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:: RCV001557879.26

Allele description [Variation Report for NM_006329.4(FBLN5):c.1093A>G (p.Ile365Val)]

NM_006329.4(FBLN5):c.1093A>G (p.Ile365Val)

Gene:

FBLN5:fibulin 5 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

14q32.12

Genomic location:

Preferred name:

NM_006329.4(FBLN5):c.1093A>G (p.Ile365Val)

HGVS:

NC_000014.9:g.91877579T>C
NG_008254.1:g.75124A>G
NM_001384158.1:c.1216A>G
NM_001384159.1:c.1144A>G
NM_001384160.1:c.1093A>G
NM_001384161.1:c.925A>G
NM_001384162.1:c.925A>G
NM_006329.4:c.1093A>GMANE SELECT
NP_001371087.1:p.Ile406Val
NP_001371088.1:p.Ile382Val
NP_001371089.1:p.Ile365Val
NP_001371090.1:p.Ile309Val
NP_001371091.1:p.Ile309Val
NP_006320.2:p.Ile365Val
LRG_364t1:c.1093A>G
LRG_364:g.75124A>G
NC_000014.8:g.92343923T>C
NM_006329.3:c.1093A>G

Protein change:

I309V

Links:

dbSNP: rs140452924

NCBI 1000 Genomes Browser:

rs140452924

Molecular consequence:

NM_001384158.1:c.1216A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001384159.1:c.1144A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001384160.1:c.1093A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001384161.1:c.925A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001384162.1:c.925A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_006329.4:c.1093A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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LOC127117839 [Pisum sativum]
LOC127117839 [Pisum sativum]
Gene ID:127117839

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001779725	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Nov 13, 2020)	germline	clinical testing	Citation Link,
SCV001961461	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Jul 1, 2021)	germline	clinical testing	Citation Link,
SCV002315284	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 24, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29555955, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001779725

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Nov 13, 2020)

germline

clinical testing

Citation Link,

SCV001961461

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Uncertain significance
(Jul 1, 2021)

germline

clinical testing

Citation Link,

SCV002315284

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Nov 24, 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	yes	1	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

Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.

Birtel J, Eisenberger T, Gliem M, Müller PL, Herrmann P, Betz C, Zahnleiter D, Neuhaus C, Lenzner S, Holz FG, Mangold E, Bolz HJ, Charbel Issa P.

Sci Rep. 2018 Mar 19;8(1):4824. doi: 10.1038/s41598-018-22096-0.

PubMed [citation]

PMID:: 29555955
PMCID:: PMC5859282

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 GeneDx, SCV001779725.1

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

Description

Has not been previously reported as pathogenic or benign in association with connective tissue disorders to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29555955)

#	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

From CeGaT Center for Human Genetics Tuebingen, SCV001961461.20

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002315284.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 365 of the FBLN5 protein (p.Ile365Val). This variant is present in population databases (rs140452924, gnomAD 0.007%). This missense change has been observed in individual(s) with FBLN5-related conditions (PMID: 29555955). ClinVar contains an entry for this variant (Variation ID: 1194964). 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 not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. 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

Last Updated: Oct 20, 2024

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