Submissions for variant NM_198252.3(GSN):c.487G>A (p.Asp163Asn)

gnomAD frequency: 0.00001  dbSNP: rs121909715

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489240	SCV000576944	pathogenic	not provided	2017-04-13	criteria provided, single submitter	clinical testing	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.
Fulgent Genetics, Fulgent Genetics	RCV000017564	SCV000893788	pathogenic	Finnish type amyloidosis	2021-10-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000017564	SCV001149797	pathogenic	Finnish type amyloidosis	2018-02-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000489240	SCV001246225	pathogenic	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000489240	SCV001714312	pathogenic	not provided	2019-04-23	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000017564	SCV001981654	pathogenic	Finnish type amyloidosis	2021-08-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000489240	SCV002242513	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	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.
Ambry Genetics	RCV002362587	SCV002661213	pathogenic	Inborn genetic diseases	2019-12-30	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000489240	SCV004243359	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
OMIM	RCV000017564	SCV000037835	pathogenic	Finnish type amyloidosis	2002-01-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000489240	SCV002034142	pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000489240	SCV002034990	pathogenic	not provided		no assertion criteria provided	clinical testing