VCV000374506.46 - ClinVar

NM_001378454.1(ALMS1):c.1732del (p.Arg578fs)

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.

(10)

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/Likely pathogenic

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.1732del (p.Arg578fs)

Variation ID: 374506 Accession: VCV000374506.46

Type and length

Deletion, 1 bp

Location

Cytogenetic: 2p13.1 2: 73448259 (GRCh38) [ NCBI UCSC ] 2: 73675386 (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	Jan 30, 2017	Oct 20, 2024	Sep 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001378454.1:c.1732del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001365383.1:p.Arg578fs	frameshift
NM_015120.4:c.1735del	NP_055935.4:p.Arg579fs	frameshift
NM_015120.4:c.1735delA
NC_000002.12:g.73448259del
NC_000002.11:g.73675386del
NG_011690.1:g.67507del
LRG_741:g.67507del
LRG_741t1:c.1735del	LRG_741p1:p.Arg579fs

... more HGVS ... less HGVS

Protein change

R579fs, R578fs

Other names

Canonical SPDI

NC_000002.12:73448258:A:

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.

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

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

The Genome Aggregation Database (gnomAD), exomes 0.00002

Links

ClinGen: CA1713220 dbSNP: rs777476179 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	6190	6510

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	Likely pathogenic (4)	criteria provided, single submitter	Aug 1, 2016	RCV000415931.26
Alstrom syndrome	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Sep 21, 2023	RCV000668033.12
Hearing impairment Leukodystrophy Stage 5 chronic kidney disease Visual impairment	Likely pathogenic (1)	no assertion criteria provided	-	RCV001003950.2
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Apr 17, 2020	RCV002402110.3

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 pathogenic (Jul 10, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Alstrom syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000792576.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 26104972
Pathogenic (May 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Alstrom syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002807601.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Sep 21, 2023)	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: SCV000931494.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024	Publications: PubMed (2) PubMed: 24462884‚ 17594715 Comment: For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 374506). This premature translational stop signal … (more) For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 374506). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 24462884). This variant is present in population databases (rs777476179, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg579Glyfs*17) 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). (less)
Pathogenic (Apr 17, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002713282.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (5) PubMed: 24462884‚ 25296579‚ 26066530‚ 26104972‚ 27178444 Comment: The c.1735delA variant, located in coding exon 8 of the ALMS1 gene, results from a deletion of one nucleotide at nucleotide position 1735, causing a … (more) The c.1735delA variant, located in coding exon 8 of the ALMS1 gene, results from a deletion of one nucleotide at nucleotide position 1735, causing a translational frameshift with a predicted alternate stop codon (p.R579Gfs*17). This variant has been reported in association with Alstrom syndrome in individuals with disease features and a second ALMS1 mutation (Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Paisey RB et al. J. Clin. Endocrinol. Metab., 2015 Aug;100:E1116-24). 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)
Likely pathogenic (Aug 01, 2016)	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: SCV000493279.33 First in ClinVar: Jan 30, 2017 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Likely pathogenic (-)	no assertion criteria provided Method: research	Hearing impairment Visual impairment Leukodystrophy Stage 5 chronic kidney disease Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV001161940.1 First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020	Publications: PubMed (1) PubMed: 32581362 Number of individuals with the variant: 1 Sex: female
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924635.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 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: SCV001968807.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 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: SCV002037291.1 First in ClinVar: Dec 21, 2021 Last updated: Dec 21, 2021
Pathogenic (Feb 02, 2021)	no assertion criteria provided Method: clinical testing	Alstrom syndrome Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002080425.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022

Comment:

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 374506). This premature translational stop signal has been observed in individual(s) with Alstrom syndrome (PMID: 24462884). This variant is present in population databases (rs777476179, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg579Glyfs*17) 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).

Comment:

The c.1735delA variant, located in coding exon 8 of the ALMS1 gene, results from a deletion of one nucleotide at nucleotide position 1735, causing a translational frameshift with a predicted alternate stop codon (p.R579Gfs*17). This variant has been reported in association with Alstrom syndrome in individuals with disease features and a second ALMS1 mutation (Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Paisey RB et al. J. Clin. Endocrinol. Metab., 2015 Aug;100:E1116-24). 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.

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
Whole-genome sequencing of patients with rare diseases in a national health system.	Turro E	Nature	2020	PMID: 32581362
Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.	Gathercole LL	Liver international : official journal of the International Association for the Study of the Liver	2016	PMID: 27178444
Diffuse left ventricular interstitial fibrosis is associated with sub-clinical myocardial dysfunction in Alström Syndrome: an observational study.	Edwards NC	Orphanet journal of rare diseases	2015	PMID: 26104972
Duration of Diabetes Predicts Aortic Pulse Wave Velocity and Vascular Events in Alström Syndrome.	Paisey RB	The Journal of clinical endocrinology and metabolism	2015	PMID: 26066530
The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.	Ozantürk A	Journal of human genetics	2015	PMID: 25296579
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

Text-mined citations for rs777476179 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_001378454.1(ALMS1):c.1732del (p.Arg578fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs777476179 ...