ClinVar Genomic variation as it relates to human health
NM_004646.4(NPHS1):c.319G>A (p.Ala107Thr)
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.
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.
Likely pathogenic(3); Uncertain significance(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004646.4(NPHS1):c.319G>A (p.Ala107Thr)
Variation ID: 56494 Accession: VCV000056494.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19q13.12 19: 35851340 (GRCh38) [ NCBI UCSC ] 19: 36342242 (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 Jul 24, 2013 Feb 14, 2024 Nov 27, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004646.4:c.319G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004637.1:p.Ala107Thr missense NC_000019.10:g.35851340C>T NC_000019.9:g.36342242C>T NG_013356.2:g.22948G>A NG_051206.1:g.4706C>T LRG_693:g.22948G>A LRG_693t1:c.319G>A LRG_693p1:p.Ala107Thr O60500:p.Ala107Thr - Protein change
- A107T
- Other names
- -
- Canonical SPDI
- NC_000019.10:35851339:C: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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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. |
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NPHS1 | - | - |
GRCh38 GRCh37 |
1634 | 1813 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Nov 3, 2021 | RCV000049907.11 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV001169934.4 | |
Uncertain significance (1) |
criteria provided, single submitter
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Aug 15, 2023 | RCV003330420.1 |
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
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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
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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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760449.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Uncertain significance
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV002060102.2
First in ClinVar: Jan 15, 2022 Last updated: Dec 24, 2022 |
Comment:
NM_004646.3(NPHS1):c.319G>A(A107T) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. A107T has been observed in cases … (more)
NM_004646.3(NPHS1):c.319G>A(A107T) is a missense variant classified as a variant of uncertain significance in the context of nephrotic syndrome, NPHS1-related. A107T has been observed in cases with relevant disease (PMID: 18614772, 20507940, 25349199). Functional assessments of this variant are available in the literature (PMID: 18614772). A107T has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_004646.3(NPHS1):c.319G>A(A107T) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. (less)
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Likely pathogenic
(Nov 27, 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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Invitae
Accession: SCV004297318.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 107 of the NPHS1 protein (p.Ala107Thr). … (more)
This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 107 of the NPHS1 protein (p.Ala107Thr). This variant is present in population databases (rs386833933, gnomAD 0.003%). This missense change has been observed in individual(s) with steroid-resistant nephrotic syndrome (PMID: 18614772, 25349199). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 56494). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NPHS1 protein function. Experimental studies have shown that this missense change does not substantially affect NPHS1 function (PMID: 18614772). This variant disrupts the p.Ala107 amino acid residue in NPHS1. Other variant(s) that disrupt this residue have been observed in individuals with NPHS1-related conditions (PMID: 20172850, 20798252), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
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Uncertain significance
(Nov 03, 2018)
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criteria provided, single submitter
Method: clinical testing
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Finnish congenital nephrotic syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914839.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
The NPHS1 c.319G>A (p.Ala107Thr) variant has been reported in a compound heterozygous state with a splice site variant in one individual with congenital Finnish nephrosis … (more)
The NPHS1 c.319G>A (p.Ala107Thr) variant has been reported in a compound heterozygous state with a splice site variant in one individual with congenital Finnish nephrosis (Philippe et al. 2008). The p.Ala107Thr variant was absent from 188 control chromosomes, but is reported at a frequency of 0.000027 in the European (non-Finnish) population from the Genome Aggregation Database. Functional studies in HeLa cells demonstrated that the p.Ala107Thr variant protein localized to the plasma membrane with wild type nephrin. In HEK293 cells, co-immunoprecipitation studies showed that both nephrin homodimerization and NEPH1 heterodimerization were intact and unaffected by the p.Ala107Thr variant (Philippe et al. 2008). Based on the limited evidence, the p.Ala107Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for congenital nephrotic syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Likely pathogenic
(May 03, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: no
Allele origin:
unknown
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Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV001251664.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
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Uncertain significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV004039537.1
First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023 |
Comment:
Variant summary: NPHS1 c.319G>A (p.Ala107Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three … (more)
Variant summary: NPHS1 c.319G>A (p.Ala107Thr) results in a non-conservative amino acid change located in the Immunoglobulin subtype 2 (IPR003598) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 249074 control chromosomes (gnomAD). c.319G>A has been reported in the literature in individuals affected with Nephrotic Syndrome, Type 1, (Philippe_2008, Sadowski_2015), and one was reported as compound heterozygous with a (likely) pathogenic variant. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 18614772, 25349199). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Finnish congenital nephrotic syndrome
Affected status: not provided
Allele origin:
not provided
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Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)
Accession: SCV000082316.1
First in ClinVar: Jul 24, 2013 Last updated: Jul 24, 2013
Comment:
FinDis database variant: FinDis database variant: This variant was not found or characterized by our laboratory, data were collected from public sources: see reference
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Comment:
Converted during submission to Likely pathogenic.
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A single-gene cause in 29.5% of cases of steroid-resistant nephrotic syndrome. | Sadowski CE | Journal of the American Society of Nephrology : JASN | 2015 | PMID: 25349199 |
Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. | Büscher AK | Clinical journal of the American Society of Nephrology : CJASN | 2010 | PMID: 20798252 |
Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. | Machuca E | Journal of the American Society of Nephrology : JASN | 2010 | PMID: 20507940 |
Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS). | Schoeb DS | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2010 | PMID: 20172850 |
Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome. | Philippe A | Journal of the American Society of Nephrology : JASN | 2008 | PMID: 18614772 |
Text-mined citations for rs386833933 ...
HelpRecord last updated Feb 20, 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.