rs864309526

Positions:

• chr14-91877555-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_006329.4(FBLN5):​c.1117C>T​(p.Arg373Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBLN5 NM_006329.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 U:1
• Conservation: PhyloP100: 6.63

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838
• PP5: Variant 14-91877555-G-A is Pathogenic according to our data. Variant chr14-91877555-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 218358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBLN5	NM_006329.4	c.1117C>T	p.Arg373Cys	missense_variant	10/11	ENST00000342058.9	NP_006320.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBLN5	ENST00000342058.9	c.1117C>T	p.Arg373Cys	missense_variant	10/11	1	NM_006329.4	ENSP00000345008	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charcot-Marie-Tooth disease, demyelinating, IIA 1H Pathogenic:3

Likely pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Oct 23, 2018	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2013	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Apr 23, 2024	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 08, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 373 of the FBLN5 protein (p.Arg373Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant FBLN5-related conditions (PMID: 21576112, 23328402, 28332470, 31945625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218358). 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. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 09, 2017	The p.Arg373Cys variant (rs864309526) has been reported to segregate with adult onset Charcot-Marie-Tooth neuropathy in three unrelated families and has been identified in an individual who was part of a peripheral neuropathy cohort (Auer-Grumbach 2011, Cheng 2017, Laššuthová 2016, and Šafka Brozková 2013). The p.Arg373Cys is also absent from general population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The arginine at codon 373 is highly conserved considering 11 species up to frog (Alamut software v2.10.0), and computational analyses predict that this variant does affect the structure/function of the FBLN5 protein (SIFT: damaging, PolyPhen2: probably damaging, MutationTaster: disease causing). Based on the available evidence, the p.Arg373Cys variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2023	Segregates with disease in many affected individuals with neuropathies from several families tested at GeneDx and reported in the published literature (PMID: 21576112, 23328402, 28332470, 32802946, 31945625); Not observed in large population cohorts (gnomAD); 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: 29412171, 23328402, 27549087, 23293578, 24244300, 21576112, 32802946, 31945625, 31589614, 32757322, 28332470) -

Hereditary sensorimotor neuropathy with hyperelastic skin Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium Ii, University Of Miami

Jan 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.20	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.44	N;N;N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T;D;D
Sift4G	Uncertain	0.036	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.95
MutPred		0.56		Gain of catalytic residue at T413 (P = 8e-04);.;.;
MVP		0.81
MPC		0.65
ClinPred		0.98	D
GERP RS		6.2
Varity_R		0.26
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs864309526; hg19: chr14-92343899;