rs121909715

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_198252.3(GSN):c.487G>A(p.Asp163Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,988 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D163Y) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GSN
NM_198252.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 9.96

Variant links:

Genes affected

GSN (HGNC:4620): (gelsolin) The protein encoded by this gene binds to the "plus" ends of actin monomers and filaments to prevent monomer exchange. The encoded calcium-regulated protein functions in both assembly and disassembly of actin filaments. Defects in this gene are a cause of familial amyloidosis Finnish type (FAF). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GSN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a binding_site (size 7) in uniprot entity GELS_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_198252.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-121310819-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 16181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 9-121310819-G-A is Pathogenic according to our data. Variant chr9-121310819-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-121310819-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GSN	NM_198252.3 linkuse as main transcript	c.487G>A	p.Asp163Asn	missense_variant	5/18	ENST00000432226.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GSN	ENST00000432226.7 linkuse as main transcript	c.487G>A	p.Asp163Asn	missense_variant	5/18	5	NM_198252.3	P1	P06396-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251420

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727226

show subpopulations

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:

0.0000374

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 214 of the GSN protein (p.Asp214Asn). This variant is present in population databases (rs121909715, gnomAD 0.008%). This missense change has been observed in individual(s) with Finnish type amyloidosis (PMID: 1652889, 2176164, 22622774, 25342098). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp187Asn. ClinVar contains an entry for this variant (Variation ID: 16180). 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 GSN protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GSN function (PMID: 29637772). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2017	The D214N variant in the GSN gene has been reported multiple times, as D187N due to the use of alternative nomenclature, in association with familial amyloidosis (Maury et al., 1990; Levy et al., 1990; Hiltunen et al., 1991; Gorevic et al., 1991; de la Chapelle et al., 1992). The D214N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The D214N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret D214N as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 23, 2019	- -

Finnish type amyloidosis

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 07, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 23, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2002	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

The p.D214N pathogenic mutation (also known as c.640G>A), located in coding exon 4 of the GSN gene, results from a G to A substitution at nucleotide position 640. The aspartic acid at codon 214 is replaced by asparagine, an amino acid with highly similar properties. This alteration co-segregated with disease in multiple unrelated families (Paunio T et al. Hum. Mutat., 1995;6:60-5). The p.D214N alteration, also referred to a p.D187N in the literature, is the most common disease-causing alteration for Finnish type amyloidosis (Maury CP et al. FEBS Lett., 1990 Dec;276:75-7; Sagnelli A et al. J. Peripher. Nerv. Syst., 2017 03;22:59-63; Lucero Saá F et al. Case Rep Ophthalmol, 2017 Aug;8:446-451; Mustonen T et al. Eur. J. Hum. Genet., 2018 01;26:117-123). Functional analysis demonstrated that the p.D214N alteration triggers the proteolytic pathway producing amyloidogenic fragments (Srivastava A et al. Biochemistry, 2018 04;57:2359-2372). Fragmentation patterns of the gelsolin peptide analogs in the circulation of patients with Finnish familial amyloidosis showed that the D187N substitution in gelsolin creates a conformation that is highly fibrillogenic (Maury CP et al. Amyloid, 2003 Aug;10 Suppl 1:21-5). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.14

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.6

D;D;.;.;.;.;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0020

D;D;.;.;.;.;D;D

Sift4G

Uncertain

0.0060

D;D;.;D;D;D;D;D

Polyphen

1.0

.;.;.;.;.;.;.;D

Vest4

0.99

MutPred

0.96

.;.;.;.;.;.;.;Gain of catalytic residue at C215 (P = 0.2119);

MVP

0.85

MPC

1.1

ClinPred

1.0

GERP RS

4.2

Varity_R

0.93

gMVP

0.90

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over