rs121909715
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong
The NM_198252.3(GSN):โc.487G>Aโ(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 (โ โ ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D163Y) has been classified as Likely pathogenic.
Frequency
Consequence
NM_198252.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GSN | NM_198252.3 | 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 | c.487G>A | p.Asp163Asn | missense_variant | 5/18 | 5 | NM_198252.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135894
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461852Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727226
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 23, 2019 | - - |
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 | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Finnish type amyloidosis Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Aug 23, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU Mรผnchen | Feb 07, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 24, 2021 | - - |
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at