Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000726756 | SCV000702798 | pathogenic | not provided | 2016-11-17 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000004177 | SCV000944254 | pathogenic | Alstrom syndrome | 2024-01-26 | 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 | |
Gene |
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 Center for Mendelian Genomics, |
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). |
Ambry Genetics | RCV002512737 | SCV003736050 | pathogenic | Inborn genetic diseases | 2020-01-22 | criteria provided, single submitter | clinical testing | The alteration results in a premature stop codon: The c.10775delC alteration, located in coding exon 16 of the ALMS1 gene, results from a deletion of one nucleotide at position 10775, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases: Based on data from the Genome Aggregation Database (gnomAD), the c.10775delC alteration was observed in 0.005% (14/280112) of total alleles studied, with a frequency of 0.01% (13/128100) in the non-Finnish European subpopulation. The alteration has been observed in affected individuals: This alteration has been observed in multiple individuals with features consistent with Alstrom syndrome (Collin, 2002; Marshall, 2007; Waldman, 2018). Based on the available evidence, this alteration is classified as pathogenic. |
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, |
RCV000004177 | SCV001453045 | pathogenic | Alstrom syndrome | 2020-09-16 | no assertion criteria provided | clinical testing |