ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.6299A>T (p.Lys2100Ile) (rs373286582)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470423 SCV000541339 uncertain significance Alstrom syndrome 2016-10-13 criteria provided, single submitter clinical testing This sequence change replaces lysine with isoleucine at codon 2101 of the ALMS1 protein (p.Lys2101Ile). The lysine residue is moderately conserved and there is a moderately physicochemical difference between lysine and isoleucine. This variant is present in population databases (rs373286582, ExAC 0.006%) but has not been reported in the literature in individuals with a ALMS1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; Align-GVGD: "Class C0"). The isoleucine amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function or cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000735887 SCV000864113 uncertain significance not specified 2017-03-13 criteria provided, single submitter clinical testing Variant summary: The ALMS1 c.6296A>T (p.Lys2099Ile, alternative name c.6302A>T) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/5 in silico tools. This variant was found in 4/118064 control chromosomes from ExAC, only observed in the European (Non-Finnish) subpopulation at a frequency of 0.000062 (4/65004). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic ALMS1 variant (0.0022361). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786093 SCV000924731 uncertain significance not provided 2016-10-12 no assertion criteria provided provider interpretation The testing laboratory was Invitae. Given that there is no case data available on this variant, and that it is present in control populations, we consider this a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy individuals (“predictive genetic testing”). Notably, the gene does not match the patient’s phenotype. The ALMS1 gene is associated with autosomal recessive Alström syndrome. To our knowledge, there are no case reports of LVNC caused by a heterozygous variant in ALMS1. There is no case data for this variant. Furthermore, loss-of-function variants in ALMS1, such as frameshift, splice site and truncating, are the most likely to cause disease. There is little evidence that missense changes, such as that of our patient, would have a clinically significant impact. The in silico prediction model SIFT predicts this variant to be deleterious. The lysine at codon 2101 is not conserved across species. There are multiple Ensemble transcripts for this gene and only one HGVS transcript. The testing lab uses a different Ensembl transcript for this gene than that which directly corresponds to the HGVS transcript (NM_015120.4 corresponds with ENST00000264448 using Mutation taster). According to the ENST00000264448 transcript, this variant would be reported as p.Lys2099Ile. The variant, using notation p.Lys2099Ile and the ENST00000264448 transcript, is present in 4 out of 59,032 individuals the ExAC dataset (, which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of October 2016). Specifically, this variant is present in 4 out of 32,502 individuals of European (non-Finnish) descent. The average coverage at that site in ExAC is 30x.
Natera, Inc. RCV000470423 SCV001463054 uncertain significance Alstrom syndrome 2020-09-16 no assertion criteria provided clinical testing

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