Submissions for variant NM_001378454.1(ALMS1):c.10480C>T (p.Gln3494Ter)

gnomAD frequency: 0.00004  dbSNP: rs772624348

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192879	SCV000246353	pathogenic	Alstrom syndrome	2014-01-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000192879	SCV001231130	pathogenic	Alstrom syndrome	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln3495*) 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 (rs772624348, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Alström syndrome (PMID: 11941370, 24462884, 28402684). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gln3494*. ClinVar contains an entry for this variant (Variation ID: 210122). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001723762	SCV002571454	pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.10477C>T p.Gln3493*; This variant is associated with the following publications: (PMID: 19440062, 33197640, 28402684, 26066530, 24462884, 17594715, 30064963, 29718281, 25846608, 26704672, 16720663, 22043170, 18195218, 28610912, 11941370)
Ambry Genetics	RCV002399711	SCV002706791	pathogenic	Cardiovascular phenotype	2021-06-16	criteria provided, single submitter	clinical testing	The p.Q3495* pathogenic mutation (also known as c.10483C>T), located in coding exon 16 of the ALMS1 gene, results from a C to T substitution at nucleotide position 10483. This changes the amino acid from a glutamine to a stop codon within coding exon 16. This mutation has been detected in the homozygous state and in the compound heterozygous state with other ALMS1 mutations in individuals reported to have Alstrom syndrome, and has been reported to segregate with disease in a kindred (Hearn T et al. Nat Genet, 2002 May;31:79-83; Paisey RB et al. Eur J Med Genet, 2014 Feb;57:71-5; Cruz-Aguilar M et al. Genet Test Mol Biomarkers, 2017 Jun;21:397-401; Dotan G et al. Ophthalmic Genet Jan;38:440-445). 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000192879	SCV004812078	pathogenic	Alstrom syndrome	2024-03-11	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_STR,PM2_SUP,PP4; Identified as compund heterozygous with NM_001378454.1:c.11669-1G>A
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV001723762	SCV005199516	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000192879	SCV001453044	pathogenic	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001723762	SCV001952649	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001723762	SCV001965119	pathogenic	not provided		no assertion criteria provided	clinical testing