Submissions for variant NM_001378454.1(ALMS1):c.355C>T (p.Gln119Ter)

gnomAD frequency: 0.00004  dbSNP: rs751804613

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000665317	SCV000789417	likely pathogenic	Alstrom syndrome	2017-01-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000665317	SCV000893618	likely pathogenic	Alstrom syndrome	2022-04-07	criteria provided, single submitter	clinical testing
Invitae	RCV000665317	SCV001199690	pathogenic	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln120*) 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 (rs751804613, gnomAD 0.004%). 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: 550543). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002460103	SCV002618174	pathogenic	Cardiovascular phenotype	2020-12-07	criteria provided, single submitter	clinical testing	The p.Q120* pathogenic mutation (also known as c.358C>T), located in coding exon 2 of the ALMS1 gene, results from a C to T substitution at nucleotide position 358. This changes the amino acid from a glutamine to a stop codon within coding exon 2. 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.
GeneDx	RCV003117464	SCV003798731	likely pathogenic	not provided	2023-01-13	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); Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665317	SCV003801101	likely pathogenic	Alstrom syndrome	2023-01-19	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.355C>T/p.Gln119X (also known as c.358C>T/p.Gln120Ter in RefSeq) 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. The variant allele was found at a frequency of 2.4e-05 in 249368 control chromosomes. To our knowledge, no occurrence of c.355C>T in individuals affected with Alstrom Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.