Submissions for variant NM_001378454.1(ALMS1):c.6772del (p.Thr2258fs)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523272	SCV000620074	likely pathogenic	not provided	2017-08-15	criteria provided, single submitter	clinical testing	Although the c.6775delA likely pathogenic variant in the ALMS1 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon threonine 2259, changing it to a leucine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Thr2259LeufsX9. This likely pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other loss of function variants in the ALMS1 gene have been reported in Human Gene Mutation Database in association with Alstrom syndrome (Stenson et al., 2014). Furthermore, the c.6775delA variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375096	SCV001571961	likely pathogenic	Stickler syndrome	2021-04-12	criteria provided, single submitter	clinical testing	PVS1_Strong, PM2_Moderate
Invitae	RCV000984143	SCV001584866	pathogenic	Alstrom syndrome	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr2259Leufs*9) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 451381). For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000984143	SCV001132119	likely pathogenic	Alstrom syndrome	2018-03-13	no assertion criteria provided	clinical testing

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