ClinVar Genomic variation as it relates to human health
NM_001378454.1(ALMS1):c.6707C>T (p.Pro2236Leu)
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.6707C>T (p.Pro2236Leu)
Variation ID: 459880 Accession: VCV000459880.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p13.1 2: 73453234 (GRCh38) [ NCBI UCSC ] 2: 73680361 (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 Dec 26, 2017 May 1, 2024 Jul 27, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001378454.1:c.6707C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365383.1:p.Pro2236Leu missense NM_015120.4:c.6710C>T NP_055935.4:p.Pro2237Leu missense NC_000002.12:g.73453234C>T NC_000002.11:g.73680361C>T NG_011690.1:g.72482C>T LRG_741:g.72482C>T LRG_741t1:c.6710C>T LRG_741p1:p.Pro2237Leu - Protein change
- P2237L, P2236L
- Other names
- p.Pro2237Leu
- Canonical SPDI
- NC_000002.12:73453233: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) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00003
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
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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 |
6006 | 6317 |
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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Uncertain significance (3) |
criteria provided, multiple submitters, no conflicts
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Mar 3, 2022 | RCV000535146.5 | |
Uncertain significance (1) |
no assertion criteria provided
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Jan 9, 2018 | RCV000786094.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jul 27, 2022 | RCV002367801.2 |
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
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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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Uncertain significance
(Mar 03, 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: SCV000631796.2
First in ClinVar: Dec 26, 2017 Last updated: Mar 26, 2023 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2237 of the ALMS1 protein (p.Pro2237Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2237 of the ALMS1 protein (p.Pro2237Leu). This variant is present in population databases (rs201737248, gnomAD 0.002%). 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: 459880). 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
(Jun 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Alstrom syndrome
Affected status: yes
Allele origin:
germline
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Clinical Genomics Program, Stanford Medicine
Accession: SCV004811882.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
The p.Pro2237Leu (also referred to as p.Pro2235Leu) variant in the ALMS1 gene has not been previously reported in association with disease. This variant has been … (more)
The p.Pro2237Leu (also referred to as p.Pro2235Leu) variant in the ALMS1 gene has not been previously reported in association with disease. This variant has been identified in 4/127,976 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that the p.Pro2237Leu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro2237Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4] (less)
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Uncertain significance
(Jul 27, 2022)
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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: SCV002665967.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.P2237L variant (also known as c.6710C>T), located in coding exon 8 of the ALMS1 gene, results from a C to T substitution at nucleotide … (more)
The p.P2237L variant (also known as c.6710C>T), located in coding exon 8 of the ALMS1 gene, results from a C to T substitution at nucleotide position 6710. The proline at codon 2237 is replaced by leucine, an amino acid with similar properties. This amino acid position is 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
(Jan 09, 2018)
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no assertion criteria provided
Method: provider interpretation
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not provided
Affected status: unknown
Allele origin:
germline
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Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000924732.1
First in ClinVar: Jun 30, 2019 Last updated: Jun 30, 2019 |
Comment:
This variant was identified in a heterozygous state in a patient with familial cardiomyopathy. SCICD Classification: Variant of uncertain significance based on lack of case … (more)
This variant was identified in a heterozygous state in a patient with familial cardiomyopathy. SCICD Classification: Variant of uncertain significance based on lack of case data, poor genotype-phenotype match, only a heterozygous variant in a gene that causes autosomal recessive disease, and rarity in the general population. We do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). Gene-level evidence: The ALMS1 gene is associated with autosomal RECESSIVE Alström syndrome. Alström syndrome includes cone-rod dystrophy, obesity, progressive sensorineural hearing impairment, dilated or restrictive cardiomyopathy, the insulin resistance syndrome, and multiple organ failure. There are 134 variant submissions for ALMS1 in ClinVar and 15 submissions specifically for cardiomyopathy. Five of these submissions are missense variants and considered “pathogenic†or “likely pathogenic.†Unfortunately, the submitters did not include supporting evidence or whether or not these variants were seen in the homozygous, heterozygous or compound heterozygous form. Therefore, evaluating the pathogenicity of heterozygous missense variants in ALMS1 as causative of cardiomyopathy is not possible. According to ExAC, ALMS1 is tolerant of both synonymous (z= -2.46) and missense (z= -6.40) change, while it is intolerant to loss-of-function change (pLI= 0.00). This observation agrees with available case data: published cases of Alström syndrome are caused by a loss-of-function of both copies of the ALMS1 gene. Case data (not including our patient): none ClinVar: not present Cases in the literature: none reported Segregation data: none reported Functional data: none reported In silico data (missense variants only): Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change" Conservation data: The proline at codon 2237 is highly conserved across species. Population data: Highest MAF in European NF population: 0.002382%. The variant was reported online in 3 of 138082 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 3 of 62976 individuals of European NF descent (0.002382%.). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in datasets like this so this does not necessarily rule out pathogenicity (Pan et al 2012). (less)
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Uncertain significance
(Sep 03, 2020)
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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: SCV002082836.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs201737248 ...
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.