NM_001378454.1(ALMS1):c.11953A>G (p.Ile3985Val) AND Alstrom syndrome

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Nov 2, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000705168.14

Allele description [Variation Report for NM_001378454.1(ALMS1):c.11953A>G (p.Ile3985Val)]

NM_001378454.1(ALMS1):c.11953A>G (p.Ile3985Val)

Genes:

ALMS1:ALMS1 centrosome and basal body associated protein [Gene - OMIM - HGNC]
LOC126806252:BRD4-independent group 4 enhancer GRCh37_chr2:73828496-73829695 [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

2p13.1

Genomic location:

Preferred name:

NM_001378454.1(ALMS1):c.11953A>G (p.Ile3985Val)

HGVS:

NC_000002.12:g.73601275A>G
NG_011690.1:g.220523A>G
NM_001378454.1:c.11953A>GMANE SELECT
NM_015120.4:c.11956A>G
NP_001365383.1:p.Ile3985Val
NP_055935.4:p.Ile3986Val
LRG_741t1:c.11956A>G
LRG_741:g.220523A>G
LRG_741p1:p.Ile3986Val
NC_000002.11:g.73828402A>G
NM_001378454.1:c.11953A>G

Protein change:

I3985V

Links:

dbSNP: rs201728850

NCBI 1000 Genomes Browser:

rs201728850

Molecular consequence:

NM_001378454.1:c.11953A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_015120.4:c.11956A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Alstrom syndrome (ALMS)
Synonyms:: Alstrom's syndrome
Identifiers:: MONDO: MONDO:0008763; MedGen: C0268425; Orphanet: 64; OMIM: 203800

Recent activity

Clear Turn Off Turn On

Cas6f AND (alive[prop]) (137)
Gene

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000834153	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Nov 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000897049	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001459608	Natera, Inc.	no assertion criteria provided	Likely benign (Apr 23, 2020)	germline	clinical testing
SCV001652731	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003925100	New York Genome Center	criteria provided, single submitter (NYGC Assertion Criteria 2020)	Uncertain significance (Dec 9, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Invitae, SCV000834153.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 3986 of the ALMS1 protein (p.Ile3986Val). This variant is present in population databases (rs201728850, gnomAD 0.2%). 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: 581362). 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 valine 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000897049.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001459608.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001652731.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From New York Genome Center, SCV003925100.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

The heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene has not been reported in affected individuals in the literature. The variant has 0.0003620 allele frequency in the gnomAD (v2.1.1 and v3.1.2) database (102 out of 281762 heterozygous alleles, no homozygotes). This variant is reported as both a Variant of uncertain significance and likely benign associated with Alstrom syndrome in the ClinVar database (Variation ID: 581362). The variant affects a weakly conserved residue (Ile3986) of ALMS1 protein and is predicted neutral by multiple in silico prediction tools (CADD score = 6.015, REVEL score= 0.243). Based on the available evidence, the heterozygous c.11953A>G (p.Ile3986Val) missense variant identified in the ALMS1 gene is reported as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 16, 2024

ClinVar

Relating variation to medicine