ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.2221dup (p.Thr741fs)

dbSNP: rs769291842
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000667941 SCV000792470 likely pathogenic Alstrom syndrome 2017-06-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV002424572 SCV002730210 pathogenic Cardiovascular phenotype 2021-11-03 criteria provided, single submitter clinical testing The c.2224dupA variant, located in coding exon 8 of the ALMS1 gene, results from a duplication of A at nucleotide position 2224, causing a translational frameshift with a predicted alternate stop codon (p.T742Nfs*2). This variant (also referred to as c.2218dupA) has been reported to co-occur with nonsense variants in the ALMS1 gene in individuals reported to have Alstrom syndrome (Edwards NC et al. Orphanet J Rare Dis, 2015 Jun;10:83; Astuti D et al. Hum Mutat, 2017 07;38:764-777). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Invitae RCV000667941 SCV003497565 pathogenic Alstrom syndrome 2023-06-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 552645). This premature translational stop signal has been observed in individual(s) with ALMS1-related conditions (PMID: 28432734). This variant is present in population databases (rs769291842, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Thr742Asnfs*2) 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).

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