This sequence change creates a premature translational stop signal (p.Gln3495*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (rs772624348, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alström syndrome (PMID: 11941370, 24462884, 28402684). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln3494*. ClinVar contains an entry for this variant (Variation ID: 210122). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001378454.1(ALMS1):c.10480C>T (p.Gln3494Ter)
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.
(9)
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
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001378454.1(ALMS1):c.10480C>T (p.Gln3494Ter)
Variation ID: 210122 Accession: VCV000210122.21
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.1 2: 73572357 (GRCh38) [ NCBI UCSC ] 2: 73799484 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 5, 2015 Aug 25, 2024 Mar 11, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001378454.1:c.10480C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365383.1:p.Gln3494Ter nonsense NM_015120.4:c.10483C>T NP_055935.4:p.Gln3495Ter nonsense NC_000002.12:g.73572357C>T NC_000002.11:g.73799484C>T NG_011690.1:g.191605C>T LRG_741:g.191605C>T LRG_741t1:c.10483C>T LRG_741p1:p.Gln3495Ter - Protein change
- Q3495*, Q3494*
- Other names
- -
- Canonical SPDI
- NC_000002.12:73572356:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
- 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. |
|||
| ALMS1 | - | - |
GRCh38 GRCh38 GRCh37 |
6183 | 6503 | |
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 (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2024 | RCV000192879.15 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Feb 20, 2024 | RCV001723762.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 16, 2021 | RCV002399711.2 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 14, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Alstrom syndrome
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000246353.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
|
|
|
Pathogenic
(Dec 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Alstrom syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001231130.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Gln3495*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Gln3495*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (rs772624348, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alström syndrome (PMID: 11941370, 24462884, 28402684). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln3494*. ClinVar contains an entry for this variant (Variation ID: 210122). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 11, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alstrom syndrome
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004812078.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP,PP4; Identified as compund heterozygous with NM_001378454.1:c.11669-1G>A
Clinical Features:
Cone-rod dystrophy (present) , Visual impairment (present) , Obesity (present) , Hearing impairment (present) , Insulin resistance (present) , Nystagmus (present)
Sex: female
|
|
|
Pathogenic
(Jun 16, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002706791.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.Q3495* pathogenic mutation (also known as c.10483C>T), located in coding exon 16 of the ALMS1 gene, results from a C to T substitution at … (more)
The p.Q3495* pathogenic mutation (also known as c.10483C>T), located in coding exon 16 of the ALMS1 gene, results from a C to T substitution at nucleotide position 10483. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been detected in the homozygous state and in the compound heterozygous state with other ALMS1 mutations in individuals reported to have Alstrom syndrome, and has been reported to segregate with disease in a kindred (Hearn T et al. Nat Genet, 2002 May;31:79-83; Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Cruz-Aguilar M et al. Genet Test Mol Biomarkers, 2017 Jun;21:397-401; Dotan G et al. Ophthalmic Genet Jan;38:440-445). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. (less)
|
|
|
Pathogenic
(Feb 20, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002571454.3
First in ClinVar: Sep 17, 2022 Last updated: Jul 23, 2024 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.10477C>T p.Gln3493*; This variant is associated with the following publications: (PMID: 19440062, 33197640, 28402684, 26066530, 24462884, 17594715, 30064963, 29718281, 25846608, 26704672, 16720663, 22043170, 18195218, 28610912, 11941370) (less)
|
|
|
Pathogenic
(Mar 30, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Skane University Hospital Lund
Accession: SCV005199516.1
First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024 |
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Alstrom syndrome
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001453044.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952649.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001965119.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
Comment:
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP,PP4; Identified as compund heterozygous with NM_001378454.1:c.11669-1G>A
Comment:
The p.Q3495* pathogenic mutation (also known as c.10483C>T), located in coding exon 16 of the ALMS1 gene, results from a C to T substitution at nucleotide position 10483. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been detected in the homozygous state and in the compound heterozygous state with other ALMS1 mutations in individuals reported to have Alstrom syndrome, and has been reported to segregate with disease in a kindred (Hearn T et al. Nat Genet, 2002 May;31:79-83; Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Cruz-Aguilar M et al. Genet Test Mol Biomarkers, 2017 Jun;21:397-401; Dotan G et al. Ophthalmic Genet Jan;38:440-445). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.10477C>T p.Gln3493*; This variant is associated with the following publications: (PMID: 19440062, 33197640, 28402684, 26066530, 24462884, 17594715, 30064963, 29718281, 25846608, 26704672, 16720663, 22043170, 18195218, 28610912, 11941370)
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:
This sequence change creates a premature translational stop signal (p.Gln3495*) in the ALMS1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALMS1 are known to be pathogenic (PMID: 17594715). This variant is present in population databases (rs772624348, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alström syndrome (PMID: 11941370, 24462884, 28402684). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln3494*. ClinVar contains an entry for this variant (Variation ID: 210122). For these reasons, this variant has been classified as Pathogenic.
Comment:
Criteria applied: PVS1,PM3_STR,PM2_SUP,PP4; Identified as compund heterozygous with NM_001378454.1:c.11669-1G>A
Comment:
The p.Q3495* pathogenic mutation (also known as c.10483C>T), located in coding exon 16 of the ALMS1 gene, results from a C to T substitution at nucleotide position 10483. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been detected in the homozygous state and in the compound heterozygous state with other ALMS1 mutations in individuals reported to have Alstrom syndrome, and has been reported to segregate with disease in a kindred (Hearn T et al. Nat Genet, 2002 May;31:79-83; Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Cruz-Aguilar M et al. Genet Test Mol Biomarkers, 2017 Jun;21:397-401; Dotan G et al. Ophthalmic Genet Jan;38:440-445). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.10477C>T p.Gln3493*; This variant is associated with the following publications: (PMID: 19440062, 33197640, 28402684, 26066530, 24462884, 17594715, 30064963, 29718281, 25846608, 26704672, 16720663, 22043170, 18195218, 28610912, 11941370)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A Nonsense ALMS1 Mutation Underlies Alström Syndrome in an Extended Mennonite Kindred Settled in North Mexico. | Cruz-Aguilar M | Genetic testing and molecular biomarkers | 2017 | PMID: 28402684 |
| Spectral-domain optical coherence tomography findings in Alström syndrome. | Dotan G | Ophthalmic genetics | 2017 | PMID: 28112973 |
| Modification of severe insulin resistant diabetes in response to lifestyle changes in Alström syndrome. | Paisey RB | European journal of medical genetics | 2014 | PMID: 24462884 |
| Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. | Marshall JD | Human mutation | 2007 | PMID: 17594715 |
| Mutation of ALMS1, a large gene with a tandem repeat encoding 47 amino acids, causes Alström syndrome. | Hearn T | Nature genetics | 2002 | PMID: 11941370 |
Text-mined citations for rs772624348 ...
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 Nov 10, 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.