Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GSN related disorder (ClinVar ID: VCV000016181, PMID:1338910, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016180, PMID:2176164, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.619, 3CNET: 0.886, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
ClinVar Genomic variation as it relates to human health
NM_198252.3(GSN):c.487G>T (p.Asp163Tyr)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(4)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_198252.3(GSN):c.487G>T (p.Asp163Tyr)
Variation ID: 16181 Accession: VCV000016181.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q33.2 9: 121310819 (GRCh38) [ NCBI UCSC ] 9: 124073097 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 May 26, 2024 Dec 4, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_198252.3:c.487G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_937895.1:p.Asp163Tyr missense NM_000177.5:c.640G>T NP_000168.1:p.Asp214Tyr missense NM_001127662.2:c.487G>T NP_001121134.1:p.Asp163Tyr missense NM_001127663.2:c.595G>T NP_001121135.2:p.Asp199Tyr missense NM_001127664.2:c.487G>T NP_001121136.1:p.Asp163Tyr missense NM_001127665.2:c.487G>T NP_001121137.1:p.Asp163Tyr missense NM_001127666.2:c.520G>T NP_001121138.1:p.Asp174Tyr missense NM_001127667.2:c.520G>T NP_001121139.1:p.Asp174Tyr missense NM_001258029.2:c.538G>T NP_001244958.1:p.Asp180Tyr missense NM_001258030.2:c.511G>T NP_001244959.1:p.Asp171Tyr missense NM_001353053.1:c.487G>T NP_001339982.1:p.Asp163Tyr missense NM_001353054.1:c.487G>T NP_001339983.1:p.Asp163Tyr missense NM_001353055.2:c.487G>T NP_001339984.1:p.Asp163Tyr missense NM_001353056.2:c.487G>T NP_001339985.1:p.Asp163Tyr missense NM_001353057.2:c.487G>T NP_001339986.1:p.Asp163Tyr missense NM_001353058.2:c.487G>T NP_001339987.1:p.Asp163Tyr missense NM_001353059.2:c.487G>T NP_001339988.1:p.Asp163Tyr missense NM_001353060.2:c.487G>T NP_001339989.1:p.Asp163Tyr missense NM_001353061.2:c.487G>T NP_001339990.1:p.Asp163Tyr missense NM_001353062.1:c.487G>T NP_001339991.1:p.Asp163Tyr missense NM_001353063.2:c.520G>T NP_001339992.1:p.Asp174Tyr missense NM_001353064.2:c.520G>T NP_001339993.1:p.Asp174Tyr missense NM_001353065.2:c.520G>T NP_001339994.1:p.Asp174Tyr missense NM_001353066.2:c.520G>T NP_001339995.1:p.Asp174Tyr missense NM_001353067.2:c.520G>T NP_001339996.1:p.Asp174Tyr missense NM_001353068.2:c.520G>T NP_001339997.1:p.Asp174Tyr missense NM_001353069.2:c.520G>T NP_001339998.1:p.Asp174Tyr missense NM_001353070.2:c.520G>T NP_001339999.1:p.Asp174Tyr missense NM_001353071.2:c.520G>T NP_001340000.1:p.Asp174Tyr missense NM_001353072.2:c.520G>T NP_001340001.1:p.Asp174Tyr missense NM_001353073.2:c.520G>T NP_001340002.1:p.Asp174Tyr missense NM_001353074.2:c.520G>T NP_001340003.1:p.Asp174Tyr missense NM_001353075.1:c.520G>T NP_001340004.1:p.Asp174Tyr missense NM_001353076.2:c.559G>T NP_001340005.1:p.Asp187Tyr missense NM_001353077.1:c.520G>T NP_001340006.1:p.Asp174Tyr missense NM_001353078.2:c.-168G>T 5 prime UTR NC_000009.12:g.121310819G>T NC_000009.11:g.124073097G>T NG_012872.2:g.114738G>T - Protein change
- D187Y, D174Y, D214Y, D163Y, D171Y, D180Y, D199Y
- Other names
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- Canonical SPDI
- NC_000009.12:121310818:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GSN | - | - |
GRCh38 GRCh37 |
723 | 759 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 3, 2022 | RCV000017565.36 | |
| Pathogenic (1) |
criteria provided, single submitter
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Dec 4, 2023 | RCV003556034.2 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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|---|---|---|---|---|---|
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Likely pathogenic
(Jan 03, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Finnish type amyloidosis
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002058678.2
First in ClinVar: Jan 15, 2022 Last updated: Apr 23, 2022 |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GSN related disorder (ClinVar ID: VCV000016181, PMID:1338910, PS1_P). … (more)
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GSN related disorder (ClinVar ID: VCV000016181, PMID:1338910, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016180, PMID:2176164, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.619, 3CNET: 0.886, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Sensorineural hearing loss disorder (present) , Dysarthria (present) , Abnormality of facial musculature (present)
|
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Pathogenic
(Nov 10, 2017)
|
criteria provided, single submitter
Method: clinical testing
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Finnish type amyloidosis
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV001149798.1
First in ClinVar: Feb 03, 2020 Last updated: Feb 03, 2020 |
Sex: male
Tissue: blood
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Pathogenic
(Dec 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004296066.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 214 of the GSN protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 214 of the GSN protein (p.Asp214Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyloidosis, Finnish type (PMID: 1338910, 26915616). This variant is also known as G654T p.Asp187Tyr. ClinVar contains an entry for this variant (Variation ID: 16181). 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%. This variant disrupts the p.Asp214 amino acid residue in GSN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652889, 2176164, 22622774, 25342098). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(May 17, 2024)
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no assertion criteria provided
Method: literature only
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AMYLOIDOSIS, FINNISH TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037837.3
First in ClinVar: Apr 04, 2013 Last updated: May 26, 2024 |
Comment on evidence:
De la Chapelle et al. (1992) found a heterozygous 654G-T transversion in GSN predicting an asp187-to-tyr substitution (D187Y) in a Danish family and a Czech … (more)
De la Chapelle et al. (1992) found a heterozygous 654G-T transversion in GSN predicting an asp187-to-tyr substitution (D187Y) in a Danish family and a Czech family with the Finnish-type of amyloidosis (105120). Different haplotypes were found in the Danish and Czech families, suggesting that the mutations arose independently. The substitution of an uncharged polar amino acid for the acidic aspartic acid at residue 187 creates a beta sheet conformation that may be preferentially or uniquely amyloidogenic for gelsolin. Mullany et al. (2021) stated that this variant is also referred to as ASP214TYR (NM_000177.5). (less)
|
Comment:
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 214 of the GSN protein (p.Asp214Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyloidosis, Finnish type (PMID: 1338910, 26915616). This variant is also known as G654T p.Asp187Tyr. ClinVar contains an entry for this variant (Variation ID: 16181). 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%. This variant disrupts the p.Asp214 amino acid residue in GSN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652889, 2176164, 22622774, 25342098). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
Same nucleotide change resulting in same amino acid change has been previously reported to be associated with GSN related disorder (ClinVar ID: VCV000016181, PMID:1338910, PS1_P). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016180, PMID:2176164, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.619, 3CNET: 0.886, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 214 of the GSN protein (p.Asp214Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant amyloidosis, Finnish type (PMID: 1338910, 26915616). This variant is also known as G654T p.Asp187Tyr. ClinVar contains an entry for this variant (Variation ID: 16181). 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%. This variant disrupts the p.Asp214 amino acid residue in GSN. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1652889, 2176164, 22622774, 25342098). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A novel GSN variant outside the G2 calcium-binding domain associated with Amyloidosis of the Finnish type. | Mullany S | Human mutation | 2021 | PMID: 33973672 |
| The First Korean Family With Hereditary Gelsolin Amyloidosis Caused by p.D214Y Mutation in the GSN Gene. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 26915616 |
| Clinical characteristics and SAP scintigraphic findings in 10 patients with AGel amyloidosis. | Rowczenio D | Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis | 2014 | PMID: 25342098 |
| Clinical features and haplotype analysis of newly identified Japanese patients with gelsolin-related familial amyloidosis of Finnish type. | Taira M | Neurogenetics | 2012 | PMID: 22622774 |
| Gelsolin-derived familial amyloidosis caused by asparagine or tyrosine substitution for aspartic acid at residue 187. | de la Chapelle A | Nature genetics | 1992 | PMID: 1338910 |
| Finnish type of familial amyloidosis: cosegregation of Asp187----Asn mutation of gelsolin with the disease in three large families. | Hiltunen T | American journal of human genetics | 1991 | PMID: 1652889 |
| Finnish hereditary amyloidosis is caused by a single nucleotide substitution in the gelsolin gene. | Maury CP | FEBS letters | 1990 | PMID: 2176164 |
Text-mined citations for rs121909715 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.