Submissions for variant NM_001378454.1(ALMS1):c.5002del (p.Arg1668fs)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008569	SCV001168342	pathogenic	not provided	2022-09-13	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation and 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); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155336	SCV003844715	likely pathogenic	Alstrom syndrome	2023-02-14	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.4999delA (p.Arg1667GlyfsX22) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant was absent in 249152 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4999delA in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003155336	SCV004426210	pathogenic	Alstrom syndrome	2023-01-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 817439). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg1669Glyfs*22) 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).

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