Submissions for variant NM_001378454.1(ALMS1):c.5142T>G (p.Tyr1714Ter)

gnomAD frequency: 0.00001  dbSNP: rs772136379

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494458	SCV000582569	pathogenic	not provided	2017-04-13	criteria provided, single submitter	clinical testing	The Y1715X variant in the ALMS1 gene has been reported in one patient with Alstrom syndrome who harbored a second nonsense variant in the ALMS1 gene in trans (Piñeiro-Gallego et al., 2012). Additionally, this variant has been classified as a likely pathogenic variant by another clinical laboratory in ClinVar (SCV000223919.1; Landrum et al., 2016). This variant is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the ALMS1 gene have been reported in Human Gene Mutation Database in association with Alstrom syndrome (Stenson et al., 2014). Furthermore, the Y1715X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server)
Invitae	RCV000192391	SCV001234870	pathogenic	Alstrom syndrome	2023-09-21	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs772136379, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Tyr1715*) 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 premature translational stop signal has been observed in individuals with ALMS1-related conditions (PMID: 22876109, 25846608, 28432734). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 212728).
CeGaT Center for Human Genetics Tuebingen	RCV000494458	SCV001247529	pathogenic	not provided	2016-12-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336519	SCV002641041	pathogenic	Cardiovascular phenotype	2021-07-23	criteria provided, single submitter	clinical testing	The p.Y1715* pathogenic mutation (also known as c.5145T>G), located in coding exon 8 of the ALMS1 gene, results from a T to G substitution at nucleotide position 5145. This changes the amino acid from a tyrosine to a stop codon within coding exon 8. This mutation has been reported to co-occur with other mutations in the ALMS1 gene in several individuals with Alstrom syndrome (Piñeiro-Gallego T et al. Mol Vis, 2012 Jul;18:1794-802; Citton V et al. J Neuroradiol, 2016 Jun;43:195-9; Astuti D et al. Hum Mutat, 2017 07;38:764-777; Dotan G et al. Ophthalmic Genet 2017 Jan;38:440-445; Han JC et al. J Clin Endocrinol Metab, 2018 07;103:2707-2719). 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	RCV000192391	SCV002798912	pathogenic	Alstrom syndrome	2021-09-27	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000192391	SCV000223919	likely pathogenic	Alstrom syndrome	2014-08-12	no assertion criteria provided	clinical testing
Counsyl	RCV000192391	SCV000793022	pathogenic	Alstrom syndrome	2017-07-25	no assertion criteria provided	clinical testing
Laboratory of Genetics in Ophthalmology, Institut Imagine	RCV001255897	SCV001432500	pathogenic	Retinal dystrophy, early-onset severe		no assertion criteria provided	research
Natera, Inc.	RCV000192391	SCV002080523	pathogenic	Alstrom syndrome	2021-07-29	no assertion criteria provided	clinical testing