ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.10772del (p.Thr3591fs)

gnomAD frequency: 0.00003  dbSNP: rs387906312
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins NTD LLC (GA) RCV000726756 SCV000702798 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing
Invitae RCV000004177 SCV000944254 pathogenic Alstrom syndrome 2021-12-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr3592Lysfs*6) 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 (rs387906312, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with ALMS1-related conditions (PMID: 11941369, 11941370, 25846608). ClinVar contains an entry for this variant (Variation ID: 3971). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics RCV001075440 SCV001241063 pathogenic Retinal dystrophy 2018-08-28 criteria provided, single submitter clinical testing
GeneDx RCV000726756 SCV001783714 pathogenic not provided 2021-12-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 21897446, 11941370, 11941369, 17594715, 21157496, 25846608, 26066530, 26104972, 26704672, 28610912, 32503575, 16720663)
Broad Institute Rare Disease Group, Broad Institute RCV000004177 SCV002507022 pathogenic Alstrom syndrome 2022-05-04 criteria provided, single submitter curation The heterozygous p.Thr3590LysfsTer6 variant in ALMS1 was identified by our study, along with another pathogenic variant, in 1 individual with Alstrom syndrome. The variant has been reported in at least 9 individuals of British and unknown ethnicity with Alstrom syndrome (PMID: 28610912, 26704672, 28112973, 11941369, 11941370), and has been identified in 0.01% (13/128100) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs387906312). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 3971) as pathogenic by multiple submitters. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3590 and leads to a premature termination codon 6 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 at least 3 affected homozygotes, in combination with reported likely pathogenic variants, and in at least 9 individuals with Alstrom syndrome increases the likelihood that the p.Thr3590LysfsTer6 variant is pathogenic (Variation ID: 871762, 210129; PMID: 28610912, 26704672, 28112973, 11941369, 11941370). In summary, the p.Thr3590LysfsTer6 variant is pathogenic based of the predicted loss of function effect and the presence of multiple homozygotes and other pathogenic variants found in combination with this variant in affected individuals. ACMG/AMP Criteria applied: PVS1, PM3_strong (Richards 2015).
OMIM RCV000004177 SCV000024343 pathogenic Alstrom syndrome 2007-11-01 no assertion criteria provided literature only
Counsyl RCV000004177 SCV001132116 pathogenic Alstrom syndrome 2017-04-17 no assertion criteria provided clinical testing
Natera, Inc. RCV000004177 SCV001453045 pathogenic Alstrom syndrome 2020-09-16 no assertion criteria provided clinical testing

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