ClinVar Genomic variation as it relates to human health
NM_001378454.1(ALMS1):c.4405C>A (p.Pro1469Thr)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001378454.1(ALMS1):c.4405C>A (p.Pro1469Thr)
Variation ID: 393373 Accession: VCV000393373.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 73450932 (GRCh38) [ NCBI UCSC ] 2: 73678059 (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 Mar 14, 2017 May 1, 2024 Jul 19, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001378454.1:c.4405C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365383.1:p.Pro1469Thr missense NM_015120.4:c.4408C>A NP_055935.4:p.Pro1470Thr missense NC_000002.12:g.73450932C>A NC_000002.11:g.73678059C>A NG_011690.1:g.70180C>A LRG_741:g.70180C>A LRG_741t1:c.4408C>A LRG_741p1:p.Pro1470Thr - Protein change
- P1470T, P1469T
- Other names
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- Canonical SPDI
- NC_000002.12:73450931:C: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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00009
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00017
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 | ||
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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
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. |
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ALMS1 | - | - |
GRCh38 GRCh38 GRCh37 |
5947 | 6254 |
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. |
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Uncertain significance (1) |
criteria provided, single submitter
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Aug 7, 2015 | RCV000445538.2 | |
Uncertain significance (6) |
criteria provided, multiple submitters, no conflicts
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Jul 19, 2022 | RCV000666784.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 29, 2020 | RCV001201200.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 10, 2021 | RCV001575003.3 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 29, 2020 | RCV002329006.2 |
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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Uncertain significance
(Aug 07, 2015)
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criteria provided, single submitter
Method: research
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Monogenic diabetes
Affected status: unknown
Allele origin:
unknown
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Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Accession: SCV000536970.1
First in ClinVar: Mar 14, 2017 Last updated: Mar 14, 2017 |
Comment:
ACMG Criteria: PP3, BP4
Number of individuals with the variant: 1
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Uncertain significance
(May 04, 2017)
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criteria provided, single submitter
Method: clinical testing
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Alstrom syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000791138.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Uncertain significance
(Jun 29, 2020)
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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: SCV001372275.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: ALMS1 c.4402C>A (p.Pro1468Thr, also known as c.4408C>A, p.P1470T) results in a non-conservative amino acid change in the encoded protein sequence. Three of five … (more)
Variant summary: ALMS1 c.4402C>A (p.Pro1468Thr, also known as c.4408C>A, p.P1470T) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249216 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (4.4e-05 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4402C>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(May 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001801911.1
First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports … (more)
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge (less)
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Uncertain significance
(Mar 11, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alstrom syndrome
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002794009.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Uncertain significance
(Jul 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Alstrom syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002273265.2
First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1470 of the ALMS1 protein (p.Pro1470Thr). … (more)
This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1470 of the ALMS1 protein (p.Pro1470Thr). This variant is present in population databases (rs373638043, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 393373). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(-)
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criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
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Alstrom syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV003928143.1
First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023 |
Comment:
Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found … (more)
Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs373638043 in Alstrom syndrome yet. (less)
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Uncertain significance
(Jul 29, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002627881.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P1470T variant (also known as c.4408C>A), located in coding exon 8 of the ALMS1 gene, results from a C to A substitution at nucleotide … (more)
The p.P1470T variant (also known as c.4408C>A), located in coding exon 8 of the ALMS1 gene, results from a C to A substitution at nucleotide position 4408. The proline at codon 1470 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less)
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Uncertain significance
(Mar 12, 2021)
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no assertion criteria provided
Method: clinical testing
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Alstrom syndrome
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002080506.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Alstrom syndrome
Affected status: unknown
Allele origin:
maternal
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GenomeConnect - Brain Gene Registry
Accession: SCV002760020.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
Variant interpreted as Uncertain significance and reported on 01-29-2021 by Lab or GTR ID Children's Hospital of Philadelphia. Assertions are reported exactly as they appear … (more)
Variant interpreted as Uncertain significance and reported on 01-29-2021 by Lab or GTR ID Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. (less)
Clinical Features:
Premature birth (present) , Overgrowth (present) , Short stature (present) , Failure to thrive (present) , Hyperthyroidism (present) , Abnormality of eye movement (present) , … (more)
Premature birth (present) , Overgrowth (present) , Short stature (present) , Failure to thrive (present) , Hyperthyroidism (present) , Abnormality of eye movement (present) , Myopia (present) , Abnormal retinal morphology (present) , Conductive hearing impairment (present) , Cognitive impairment (present) , Anxiety (present) , Depression (present) , Short attention span (present) , Abnormality of the cardiovascular system (present) , Abnormal cardiovascular system morphology (present) , Abnormality of the respiratory system (present) , Feeding difficulties (present) (less)
Indication for testing: Diagnostic
Age: 10-19 years
Sex: female
Method: Exome Sequencing
Testing laboratory: Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia
Date variant was reported to submitter: 2021-01-29
Testing laboratory interpretation: Uncertain significance
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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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Novel Mutations of the ALMS1 Gene in Patients with Alström Syndrome. | Wang C | Internal medicine (Tokyo, Japan) | 2021 | PMID: 34148947 |
Prevalent ALMS1 Pathogenic Variants in Spanish Alström Patients. | Bea-Mascato B | Genes | 2021 | PMID: 33669459 |
ALMS1 and Alström syndrome: a recessive form of metabolic, neurosensory and cardiac deficits. | Hearn T | Journal of molecular medicine (Berlin, Germany) | 2019 | PMID: 30421101 |
Alström Syndrome: Mutation Spectrum of ALMS1. | Marshall JD | Human mutation | 2015 | PMID: 25846608 |
Text-mined citations for rs373638043 ...
HelpRecord last updated May 01, 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.