rs80338765

Variant names:

• chr14-91891236-C-T
• rs80338765
• NM_006329.4:c.604G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_006329.4(FBLN5):​c.604G>A​(p.Gly202Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,605,346 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G202V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: FBLN5 NM_006329.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2 O:1
• Conservation: PhyloP100: 2.13
• Publications: 14 publications found

Genes affected

FBLN5 (HGNC:3602): (fibulin 5) The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

FBLN5 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• cutis laxa, autosomal recessive, type 1A

  Inheritance: SD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Charcot-Marie-Tooth disease, demyelinating, IIA 1H

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• demyelinating hereditary motor and sensory neuropathy

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• macular degeneration, age-related, 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary sensorimotor neuropathy with hyperelastic skin

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal recessive cutis laxa type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.24265203).
• BP6: Variant 14-91891236-C-T is Benign according to our data. Variant chr14-91891236-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 21453.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 11	1	NM_006329.4	ENSP00000345008.4

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000278 AC: 70 AN: 251462 AF XY: 0.000250

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.000977

GnomAD4 exome AF: 0.000223 AC: 324 AN: 1453188 Hom.: 1 Cov.: 29 AF XY: 0.000209 AC XY: 151 AN XY: 723672

African (AFR) AF: 0.0000601 AC: 2 AN: 33302

American (AMR) AF: 0.00105 AC: 47 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.000236 AC: 261 AN: 1104068

Other (OTH) AF: 0.000166 AC: 10 AN: 60084

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74326

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.000959 AC: 2 AN: 2086

Alfa AF: 0.000199 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000329 AC: 40

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Nov 29, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in association with cutis laxa and in control cohorts (Hu et al., 2006; Lotery et al., 2006); While one functional study suggests that G202R may increase binding to tropoelastin (Jones et al., 2010), another study demonstrated that this variant did not affect the structure or calcium-binding properties of fibulin-5 (Schneider et al., 2010); both authors concluded that this variant is not sufficient to cause disease (Schneider et al., 2010; Jones et al., 2010); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20007835, 16652333, 16374472, 20599547, 17035250) -

Jan 18, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 202 of the FBLN5 protein (p.Gly202Arg). This variant is present in population databases (rs80338765, gnomAD 0.09%). This missense change has been observed in individual(s) with cutis laxa and aortic aneurysm (PMID: 16374472). ClinVar contains an entry for this variant (Variation ID: 21453). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt FBLN5 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FBLN5 function (PMID: 16374472, 16652333, 20007835, 20599547). 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. -

Jan 07, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The FBLN5 c.604G>A; p.Gly202Arg variant (rs80338765) is reported in the literature in an individual affected with acquired cutis laxa who also carried two variants in the ELN gene (Hu 2006), but is also reported in healthy controls (Jones 2010, Lotery 2006). One functional study demonstrates no effects on structure or secretion (Schneider 2010), but other studies show increased binding of the variant protein to tropoelastin (Hu 2006, Jones 2010). This variant is also reported in ClinVar (Variation ID: 21453), and is found in the Latino/Admixed American population with an allele frequency of 0.11% (39/35438 alleles) in the Genome Aggregation Database. The glycine at codon 202 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.856). Based on available information, the clinical significance of the p.Gly202Arg variant is uncertain at this time. References: Hu Q et al. Inflammatory destruction of elastic fibers in acquired cutis laxa is associated with missense alleles in the elastin and fibulin-5 genes. J Invest Dermatol. 2006 Feb;126(2):283-90. PMID: 16374472. Jones RP et al. Structural effects of fibulin 5 missense mutations associated with age-related macular degeneration and cutis laxa. Invest Ophthalmol Vis Sci. 2010 May;51(5):2356-62. PMID: 20007835. Lotery AJ et al. Reduced secretion of fibulin 5 in age-related macular degeneration and cutis laxa. Hum Mutat. 2006 Jun;27(6):568-74. PMID: 16652333. Schneider R et al. Biophysical characterisation of fibulin-5 proteins associated with disease. J Mol Biol. 2010 Aug 27;401(4):605-17. PMID: 20599547. -

Cutis laxa, autosomal dominant Uncertain:1

Jan 06, 2016

Inherited Neuropathy Consortium Ii, University Of Miami

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Macular degeneration, age-related, 3 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cutis laxa Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cutis laxa, autosomal recessive, type 1A Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.1	.;M;.
PhyloP100		2.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.52
MutPred		0.63		Gain of catalytic residue at R244 (P = 0.0179);.;.;
MVP		0.88
MPC		1.2
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.28
gMVP		0.92
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338765; hg19: chr14-92357580;