ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11648_11649insGTTA (p.Asn3884fs)

gnomAD frequency: 0.00001  dbSNP: rs760264695
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665420 SCV000789540 pathogenic Alstrom syndrome 2017-02-08 criteria provided, single submitter clinical testing
Invitae RCV000665420 SCV002168246 pathogenic Alstrom syndrome 2023-12-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn3885Leufs*9) 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). This variant is present in population databases (rs760264695, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Alstrom syndrome (PMID: 25846608, 26111748, 30064963). ClinVar contains an entry for this variant (Variation ID: 550627). For these reasons, this variant has been classified as Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000665420 SCV002507020 pathogenic Alstrom syndrome 2022-05-04 criteria provided, single submitter curation The heterozygous p.Asn3883LeufsTer9 variant in ALMS1 was identified by our study in the compound heterozygous state, along with another pathogenic variant, in 1 individual with Alstrom syndrome. The variant has been reported in 6 individuals of unknown ethnicity with Alstrom syndrome (PMID: 26704672, 28610912, 26111748), and has been identified in 0.003% (3/112826) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs760264695). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3883 and leads to a premature termination codon 9 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ALMS1 gene is an established disease mechanism in autosomal recessive Alstrom syndrome. The presence of this variant in combination with reported likely pathogenic variants and in 6 individuals with Alstrom syndrome increases the likelihood that the p.Asn3883LeufsTer9 variant is pathogenic (VariationID: 556350, 553694; PMID: 26704672, 28610912, 26111748). In summary, this variant meets criteria to be classified as pathogenic for Alstrom syndrome in an autosomal recessive manner based on the predicted impact of the variant and its occurrence in trans with other likely pathogenic variants. ACMG/AMP Criteria applied: PVS1, PM2, PM3 (Richards 2015).
Ambry Genetics RCV002325338 SCV002632457 pathogenic Cardiovascular phenotype 2020-08-27 criteria provided, single submitter clinical testing The c.11651_11652insGTTA pathogenic mutation, located in coding exon 17 of the ALMS1 gene, results from an insertion of 4 nucleotides at position 11651, causing a translational frameshift with a predicted alternate stop codon (p.N3885Lfs*9). This variant has been reported in an Alstrom syndrome cohort with limited clinical details provided (Marshall JD et al. Hum. Mutat., 2015 Jul;36:660-8). 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.
Fulgent Genetics, Fulgent Genetics RCV000665420 SCV002777804 pathogenic Alstrom syndrome 2022-02-17 criteria provided, single submitter clinical testing

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