Converted during submission to Likely benign.
ClinVar Genomic variation as it relates to human health
NM_001378454.1(ALMS1):c.10751A>T (p.Gln3584Leu)
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.
(11)
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.
Benign/Likely benign
11
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.10751A>T (p.Gln3584Leu)
Variation ID: 235538 Accession: VCV000235538.39
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2p13.1 2: 73572628 (GRCh38) [ NCBI UCSC ] 2: 73799755 (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 Jun 9, 2016 Oct 20, 2024 Jan 31, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001378454.1:c.10751A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001365383.1:p.Gln3584Leu missense NM_015120.4:c.10754A>T NP_055935.4:p.Gln3585Leu missense NC_000002.12:g.73572628A>T NC_000002.11:g.73799755A>T NG_011690.1:g.191876A>T LRG_741:g.191876A>T LRG_741t1:c.10754A>T LRG_741p1:p.Gln3585Leu - Protein change
- Q3585L, Q3584L
- Other names
- -
- Canonical SPDI
- NC_000002.12:73572627:A: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.
-
0.00260 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00066
Exome Aggregation Consortium (ExAC) 0.00073
1000 Genomes Project 0.00260
The Genome Aggregation Database (gnomAD) 0.00310
1000 Genomes Project 30x 0.00312
Trans-Omics for Precision Medicine (TOPMed) 0.00317
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00320
- 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 |
6186 | 6506 | |
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. |
|---|---|---|---|---|
| Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Feb 1, 2023 | RCV000224455.17 | |
| Benign/Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Mar 11, 2021 | RCV000436742.15 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV001084997.10 | |
| Likely benign (1) |
criteria provided, single submitter
|
Jan 23, 2019 | RCV002417981.2 | |
| Likely benign (1) |
criteria provided, single submitter
|
Feb 9, 2018 | RCV000445421.4 |
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. |
|
|---|---|---|---|---|---|
|
Likely Benign
(Aug 26, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281198.1
First in ClinVar: Jun 09, 2016 Last updated: Jun 09, 2016 |
Comment:
Converted during submission to Likely benign.
|
|
|
Likely benign
(Feb 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000593115.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Benign
(Nov 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000857952.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely benign
(Mar 21, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967144.1
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African … (more)
p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144486524). (less)
Number of individuals with the variant: 1
|
|
|
Likely benign
(Feb 09, 2018)
|
criteria provided, single submitter
Method: research
|
Monogenic diabetes
Affected status: unknown
Allele origin:
unknown
|
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Accession: SCV000536991.2
First in ClinVar: Mar 14, 2017 Last updated: Jun 12, 2020 |
Comment:
ACMG criteria: BS2 (type2diabetesgenetics.org), BP4 (6 predictors), BP1 (most causal variants are truncating variants), Note:similar MAF in TODAY/1000G=likely benign
Number of individuals with the variant: 4
|
|
|
Benign
(Mar 11, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000864100.2
First in ClinVar: Dec 19, 2017 Last updated: Mar 19, 2021 |
Comment:
Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more)
Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 248684 control chromosomes, predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.10748A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Likely benign
(-)
|
criteria provided, single submitter
(K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1)
Method: research
|
Alstrom syndrome
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
|
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
Accession: SCV002605268.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
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 rs144486524 in Alstrom syndrome yet. (less)
|
|
|
Benign
(May 18, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000535048.6
First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023 |
|
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Alstrom syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000290062.10
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Jan 23, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002723773.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
|
Likely benign
(Feb 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004155006.10
First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024 |
Comment:
ALMS1: BP4, BS2
Number of individuals with the variant: 1
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144486524).
Comment:
ACMG criteria: BS2 (type2diabetesgenetics.org), BP4 (6 predictors), BP1 (most causal variants are truncating variants), Note:similar MAF in TODAY/1000G=likely benign
Comment:
Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 248684 control chromosomes, predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.10748A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
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 to ascertain the role of rs144486524 in Alstrom syndrome yet.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
ALMS1: BP4, BS2
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:
Converted during submission to Likely benign.
Comment:
p.Gln3583Leu in exon 16 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.87% (84/9696) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs144486524).
Comment:
ACMG criteria: BS2 (type2diabetesgenetics.org), BP4 (6 predictors), BP1 (most causal variants are truncating variants), Note:similar MAF in TODAY/1000G=likely benign
Comment:
Variant summary: ALMS1 c.10748A>T (p.Gln3583Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 248684 control chromosomes, predominantly at a frequency of 0.0094 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.10748A>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
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 to ascertain the role of rs144486524 in Alstrom syndrome yet.
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Comment:
ALMS1: BP4, BS2
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ALMS1 | - | - | - | - |
| type2diabetesgenetics.org | - | - | - | - |
Text-mined citations for rs144486524 ...
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 Oct 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.