VCV000220880.30 - ClinVar

NM_001378454.1(ALMS1):c.1144A>G (p.Thr382Ala)

Germline

Classification

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.

(12)

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

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.1144A>G (p.Thr382Ala)

Variation ID: 220880 Accession: VCV000220880.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p13.1 2: 73424809 (GRCh38) [ NCBI UCSC ] 2: 73651937 (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 8, 2016	Dec 22, 2024	Sep 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378454.1:c.1144A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365383.1:p.Thr382Ala	missense
NM_015120.4:c.1147A>G	NP_055935.4:p.Thr383Ala	missense
NC_000002.12:g.73424809A>G
NC_000002.11:g.73651937A>G
NG_011690.1:g.44055A>G
LRG_741:g.44055A>G
LRG_741t1:c.1147A>G	LRG_741p1:p.Thr383Ala

... more HGVS ... less HGVS

Protein change

T383A, T382A

Other names

Canonical SPDI

NC_000002.12:73424808:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.01957 (G)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.01968

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.01434

The Genome Aggregation Database (gnomAD) 0.01527

Trans-Omics for Precision Medicine (TOPMed) 0.01579

1000 Genomes Project 0.01957

The Genome Aggregation Database (gnomAD), exomes 0.00379

Exome Aggregation Consortium (ExAC) 0.00438

Links

ClinGen: CA350101 dbSNP: rs28730849 VarSome

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
Gene	OMIM	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	6216	6536

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.
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Sep 1, 2024	RCV000224192.15
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Oct 6, 2016	RCV000444233.6
Monogenic diabetes	Benign (1)	criteria provided, single submitter	Feb 8, 2019	RCV000445400.3
Alstrom syndrome	Benign (3)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001082528.10
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 26, 2018	RCV002453744.2

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.
Benign (Jan 11, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281160.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Benign (Oct 06, 2016)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000532109.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (Mar 21, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000967032.1 First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019	Comment: p.Thr382Ala in exon 5 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 7.19% (95/1322) of … (more) p.Thr382Ala in exon 5 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 7.19% (95/1322) of African chromoso mes by the 1000 Genomes Project (Phase 3; dbSNP rs28730849). (less) Number of individuals with the variant: 1
Benign (Feb 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Monogenic diabetes Affected status: unknown Allele origin: unknown	Personalized Diabetes Medicine Program, University of Maryland School of Medicine Accession: SCV000536962.2 First in ClinVar: Mar 14, 2017 Last updated: Jun 12, 2020	Comment: ACMG criteria: BP4 (REVEL score 0.007 + 9 predictors), BA1 (5.1% in African gnomAD), BS2 (36 homozygotes in gnomAD), BP1 (missense in gene with truncating … (more) ACMG criteria: BP4 (REVEL score 0.007 + 9 predictors), BA1 (5.1% in African gnomAD), BS2 (36 homozygotes in gnomAD), BP1 (missense in gene with truncating cause disease)= Benign (less) Number of individuals with the variant: 11 Zygosity: Single Heterozygote
Benign (Feb 01, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Alstrom syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000261783.11 First in ClinVar: Feb 02, 2016 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005242438.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
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: SCV002605251.1 First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022	Publications: PubMed (4) PubMed: 34148947‚ 25846608‚ 30421101‚ 33669459 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 rs28730849 in Alstrom syndrome yet. (less)
Benign (Dec 26, 2018)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002615623.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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)
Benign (Sep 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004701419.9 First in ClinVar: Mar 10, 2024 Last updated: Dec 22, 2024	Comment: ALMS1: BP4, BS1, BS2 Number of individuals with the variant: 3
Benign (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Alstrom syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458903.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002034128.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV002035702.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021
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Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This alteration is classified as 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.

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:

Citations for germline classification of this variant

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

Text-mined citations for rs28730849 ...

These 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 Dec 22, 2024

ClinVar Genomic variation as it relates to human health

NM_001378454.1(ALMS1):c.1144A>G (p.Thr382Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs28730849 ...