ClinVar Miner

Submissions for variant NM_015120.4(ALMS1):c.10357A>G (p.Asn3453Asp) (rs573748379)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766679 SCV000582073 uncertain significance not provided 2017-05-10 criteria provided, single submitter clinical testing The N3453D variant of uncertain significance in the ALMS1 gene has not been published as pathogenic or been reported as benign to our knowledge. The N3453D variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species, and aspartic acid is the wild-type amino acid at this position in multiple species. In silico analysis predicts this variant likely does not alter the protein structure/function. Furthermore, N3453D was observed in 5/9,476 alleles from individuals of African ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Integrated Genetics/Laboratory Corporation of America RCV000494528 SCV000864098 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing Variant summary: The ALMS1 c.10351A>G (p.Asn3451Asp, alternative name c.10357A>G) variant involves the alteration of a non-conserved nucleotide and is predicted to be benign by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). It is located outside of some of known domains and repeats in ALMS1 protein (InterPro, UniProt). This variant was found in 6/117580 control chromosomes at a frequency of 0.000051, which does not exceed 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.

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