NM_006329.4(FBLN5):c.1174T>C (p.Phe392Leu) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 25, 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:: RCV001776370.6

Allele description [Variation Report for NM_006329.4(FBLN5):c.1174T>C (p.Phe392Leu)]

NM_006329.4(FBLN5):c.1174T>C (p.Phe392Leu)

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.1174T>C (p.Phe392Leu)

HGVS:

NC_000014.9:g.91877498A>G
NG_008254.1:g.75205T>C
NM_001384158.1:c.1297T>C
NM_001384159.1:c.1225T>C
NM_001384160.1:c.1174T>C
NM_001384161.1:c.1006T>C
NM_001384162.1:c.1006T>C
NM_006329.4:c.1174T>CMANE SELECT
NP_001371087.1:p.Phe433Leu
NP_001371088.1:p.Phe409Leu
NP_001371089.1:p.Phe392Leu
NP_001371090.1:p.Phe336Leu
NP_001371091.1:p.Phe336Leu
NP_006320.2:p.Phe392Leu
LRG_364t1:c.1174T>C
LRG_364:g.75205T>C
NC_000014.8:g.92343842A>G
NM_006329.3:c.1174T>C

Protein change:

F336L

Links:

dbSNP: rs780349776

NCBI 1000 Genomes Browser:

rs780349776

Molecular consequence:

NM_001384158.1:c.1297T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384159.1:c.1225T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384160.1:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384161.1:c.1006T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001384162.1:c.1006T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_006329.4:c.1174T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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telethonin [Phodopus roborovskii]
telethonin [Phodopus roborovskii]
gi|2318653886|ref|XP_051031695.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002012887	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 2, 2019)	germline	clinical testing	Citation Link,
SCV002223638	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 25, 2024)	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

SCV002012887

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Dec 2, 2019)

germline

clinical testing

Citation Link,

SCV002223638

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 25, 2024)

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	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

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, SCV002012887.2

#	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 published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002223638.3

#	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 phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 392 of the FBLN5 protein (p.Phe392Leu). This variant is present in population databases (rs780349776, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FBLN5-related conditions. ClinVar contains an entry for this variant (Variation ID: 1320391). 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 FBLN5 protein function with a positive 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: Sep 29, 2024

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