The c.3G>A (p.Met1?) variant is in the initiation codon and abolishes the transcription start site. The p.Met1? variant, (described as p.Met1Ile), is reported in three studies in which it is found in a total of four individuals with Bartter syndrome. The variant was found in a homozygous state in two individuals and in a compound heterozygous state in one other individual all with Bartter syndrome with hearing loss and in a homozygous state in a fourth individual with Bartter syndrome but for whom no further phenotype data were provided (Birkenhager et al. 2001; Zaffanello et al. 2006; Brochard et al. 2009; Bettinelli et al. 2014).). The p.Met1? variant was absent from 422 control chromosomes and is reported at a frequency of 0.000070 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of the variant on protein translation, the p.Met1? variant is classified as likely pathogenic for Bartter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
ClinVar Genomic variation as it relates to human health
NM_057176.3(BSND):c.3G>A (p.Met1Ile)
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.
(6)
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
6
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_057176.3(BSND):c.3G>A (p.Met1Ile)
Variation ID: 4384 Accession: VCV000004384.19
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p32.3 1: 54999189 (GRCh38) [ NCBI UCSC ] 1: 55464862 (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 May 14, 2016 Feb 14, 2024 Jan 2, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_057176.3:c.3G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_476517.1:p.Met1Ile missense initiator codon variant NC_000001.11:g.54999189G>A NC_000001.10:g.55464862G>A NG_008965.2:g.5257G>A LRG_1282:g.5257G>A LRG_1282t1:c.3G>A LRG_1282p1:p.Met1Ile - Protein change
- M1I
- Other names
- -
- Canonical SPDI
- NC_000001.11:54999188:G:A
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00004
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00004
Trans-Omics for Precision Medicine (TOPMed) 0.00006
- 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. |
|||
| BSND | - | - |
GRCh38 GRCh37 |
345 | 361 | |
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
|
May 24, 2022 | RCV000004634.12 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 2, 2024 | RCV001057884.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 16, 2020 | RCV001272340.1 |
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
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
(Dec 18, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Bartter disease type 4A
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914414.2
First in ClinVar: May 27, 2019 Last updated: Sep 03, 2023 |
Comment:
The c.3G>A (p.Met1?) variant is in the initiation codon and abolishes the transcription start site. The p.Met1? variant, (described as p.Met1Ile), is reported in three … (more)
The c.3G>A (p.Met1?) variant is in the initiation codon and abolishes the transcription start site. The p.Met1? variant, (described as p.Met1Ile), is reported in three studies in which it is found in a total of four individuals with Bartter syndrome. The variant was found in a homozygous state in two individuals and in a compound heterozygous state in one other individual all with Bartter syndrome with hearing loss and in a homozygous state in a fourth individual with Bartter syndrome but for whom no further phenotype data were provided (Birkenhager et al. 2001; Zaffanello et al. 2006; Brochard et al. 2009; Bettinelli et al. 2014).). The p.Met1? variant was absent from 422 control chromosomes and is reported at a frequency of 0.000070 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of the variant on protein translation, the p.Met1? variant is classified as likely pathogenic for Bartter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
|
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Pathogenic
(May 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Bartter disease type 4A
Bartter disease type 4A
Affected status: unknown
Allele origin:
germline
|
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV003920514.2
First in ClinVar: Apr 30, 2023 Last updated: Sep 03, 2023 |
Comment:
This variant is predicted to abolish the translation initiation codon, resulting in an abnormal or absent protein; loss of function is an established mechanism of … (more)
This variant is predicted to abolish the translation initiation codon, resulting in an abnormal or absent protein; loss of function is an established mechanism of disease for this gene (Janssen 2009 PMID: 18776122). Variants altering the initiation codon have been reported in the literature in the homozygous state in at least 9 individuals with Bartter syndrome (Selected publications: Birkenhäger 2001 PMID: 11687798; Zaffanello 2006 PMID: 16583241; Bettinelli 2014 PMID: 24902942). This variant is present in the Genome Aggregation Database (Highest MAF: 0.007% [5/68032] https://gnomad.broadinstitute.org/variant/1-54999189-G-A?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 4384). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, this variant is classified as pathogenic. (less)
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Pathogenic
(Apr 06, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV004168673.1
First in ClinVar: Nov 25, 2023 Last updated: Nov 25, 2023 |
Comment:
Identified with a second variant (phase unknown) in a patient with Bartter syndrome and sensorineural hearing loss in published literature (Birkenhager et al., 2001); Initiation … (more)
Identified with a second variant (phase unknown) in a patient with Bartter syndrome and sensorineural hearing loss in published literature (Birkenhager et al., 2001); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 16773427, 11687798, 24902942, 19096086, 16583241) (less)
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Pathogenic
(Jan 02, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001222405.6
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change affects the initiator methionine of the BSND mRNA. The next in-frame methionine is located at codon 26. This variant is present in … (more)
This sequence change affects the initiator methionine of the BSND mRNA. The next in-frame methionine is located at codon 26. This variant is present in population databases (rs74315286, gnomAD 0.008%). Disruption of the initiator codon has been observed in individuals with Bartter syndrome (PMID: 11687798, 16773427, 24902942). ClinVar contains an entry for this variant (Variation ID: 4384). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 01, 2001)
|
no assertion criteria provided
Method: literature only
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BARTTER SYNDROME, TYPE 4A, WITH SENSORINEURAL DEAFNESS
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024808.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 03, 2023 |
Comment on evidence:
In a family from the United Kingdom with Bartter syndrome with sensorineural deafness (BARTS4A; 602522), Birkenhager et al. (2001) identified compound heterozygosity for 2 mutations … (more)
In a family from the United Kingdom with Bartter syndrome with sensorineural deafness (BARTS4A; 602522), Birkenhager et al. (2001) identified compound heterozygosity for 2 mutations in the BSND gene. One mutation was a G-to-A transition at nucleotide 3 (G3A) resulting in a methionine-to-isoleucine substitution at codon 1 (M1I). This mutation caused the loss of the start codon. The other allele carried a missense mutation, gly10-to-ser (606412.0006). (less)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
|
Bartter syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001454251.2
First in ClinVar: Jan 02, 2021 Last updated: Sep 03, 2023 |
|
Comment:
Comment:
This variant is predicted to abolish the translation initiation codon, resulting in an abnormal or absent protein; loss of function is an established mechanism of disease for this gene (Janssen 2009 PMID: 18776122). Variants altering the initiation codon have been reported in the literature in the homozygous state in at least 9 individuals with Bartter syndrome (Selected publications: Birkenhäger 2001 PMID: 11687798; Zaffanello 2006 PMID: 16583241; Bettinelli 2014 PMID: 24902942). This variant is present in the Genome Aggregation Database (Highest MAF: 0.007% [5/68032] https://gnomad.broadinstitute.org/variant/1-54999189-G-A?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 4384). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, this variant is classified as pathogenic.
Comment:
Identified with a second variant (phase unknown) in a patient with Bartter syndrome and sensorineural hearing loss in published literature (Birkenhager et al., 2001); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 16773427, 11687798, 24902942, 19096086, 16583241)
Comment:
This sequence change affects the initiator methionine of the BSND mRNA. The next in-frame methionine is located at codon 26. This variant is present in population databases (rs74315286, gnomAD 0.008%). Disruption of the initiator codon has been observed in individuals with Bartter syndrome (PMID: 11687798, 16773427, 24902942). ClinVar contains an entry for this variant (Variation ID: 4384). 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:
The c.3G>A (p.Met1?) variant is in the initiation codon and abolishes the transcription start site. The p.Met1? variant, (described as p.Met1Ile), is reported in three studies in which it is found in a total of four individuals with Bartter syndrome. The variant was found in a homozygous state in two individuals and in a compound heterozygous state in one other individual all with Bartter syndrome with hearing loss and in a homozygous state in a fourth individual with Bartter syndrome but for whom no further phenotype data were provided (Birkenhager et al. 2001; Zaffanello et al. 2006; Brochard et al. 2009; Bettinelli et al. 2014).). The p.Met1? variant was absent from 422 control chromosomes and is reported at a frequency of 0.000070 in the European (non-Finnish) population of the Genome Aggregation Database. Based on the evidence and the potential impact of the variant on protein translation, the p.Met1? variant is classified as likely pathogenic for Bartter syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Comment:
This variant is predicted to abolish the translation initiation codon, resulting in an abnormal or absent protein; loss of function is an established mechanism of disease for this gene (Janssen 2009 PMID: 18776122). Variants altering the initiation codon have been reported in the literature in the homozygous state in at least 9 individuals with Bartter syndrome (Selected publications: Birkenhäger 2001 PMID: 11687798; Zaffanello 2006 PMID: 16583241; Bettinelli 2014 PMID: 24902942). This variant is present in the Genome Aggregation Database (Highest MAF: 0.007% [5/68032] https://gnomad.broadinstitute.org/variant/1-54999189-G-A?dataset=gnomad_r3); please note, disease-causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. It is also present in ClinVar, with multiple laboratories classifying it as pathogenic or likely pathogenic (Variation ID: 4384). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In summary, this variant is classified as pathogenic.
Comment:
Identified with a second variant (phase unknown) in a patient with Bartter syndrome and sensorineural hearing loss in published literature (Birkenhager et al., 2001); Initiation codon variant in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 16773427, 11687798, 24902942, 19096086, 16583241)
Comment:
This sequence change affects the initiator methionine of the BSND mRNA. The next in-frame methionine is located at codon 26. This variant is present in population databases (rs74315286, gnomAD 0.008%). Disruption of the initiator codon has been observed in individuals with Bartter syndrome (PMID: 11687798, 16773427, 24902942). ClinVar contains an entry for this variant (Variation ID: 4384). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Phosphate homeostasis in Bartter syndrome: a case-control study. | Bettinelli A | Pediatric nephrology (Berlin, Germany) | 2014 | PMID: 24902942 |
| Phenotype-genotype correlation in antenatal and neonatal variants of Bartter syndrome. | Brochard K | Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association | 2009 | PMID: 19096086 |
| Barttin mutations in antenatal Bartter syndrome with sensorineural deafness. | Ozlu F | Pediatric nephrology (Berlin, Germany) | 2006 | PMID: 16773427 |
| Type IV Bartter syndrome: report of two new cases. | Zaffanello M | Pediatric nephrology (Berlin, Germany) | 2006 | PMID: 16583241 |
| Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure. | Birkenhäger R | Nature genetics | 2001 | PMID: 11687798 |
Text-mined citations for rs74315286 ...
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.