Submissions for variant NM_015120.4(ALMS1):c.1270G>A (p.Val424Ile) (rs45630557)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000234139	SCV000290072	benign	Alstrom syndrome	2018-01-05	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000435494	SCV000510969	likely benign	not provided	2016-09-12	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
GeneDx	RCV000434450	SCV000528959	likely benign	not specified	2018-01-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago	RCV000434450	SCV000593109	likely benign	not specified	2016-12-30	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000434450	SCV000864106	benign	not specified	2018-05-21	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.1267G>A (p.Val423Ile, alternative name c.1270G>A) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0028 in 276990 control chromosomes, predominantly found within the South Asian subpopulation with a frequency of 0.0051 in the gnomAD database, including 4 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. At least one publication reports experimental evidence, demonstrating no sign of exon skipping with normal ALMS1 expression and without discernible defects in ciliary morphology in a cell line established from an individual carrying the variant (Chen 2017). These results indicate no damaging effect for this variant. 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 benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000434450	SCV000967143	likely benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Val423Ile in exon 6 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 0.50% (82/16512) of South Asian chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs45630557).