ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.1267G>A (p.Val423Ile)

gnomAD frequency: 0.00285  dbSNP: rs45630557
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082105 SCV000290072 benign Alstrom syndrome 2021-12-18 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 RCV000435494 SCV000528959 likely benign not provided 2020-11-30 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28717663, 25846608, 18154657, 21157496, 25296579)
Genetic Services Laboratory,University of Chicago RCV000434450 SCV000593109 likely benign not specified 2016-12-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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,Mass General Brigham 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).
Athena Diagnostics Inc RCV000435494 SCV001142998 benign not provided 2018-09-20 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000435494 SCV001152347 likely benign not provided 2019-08-01 criteria provided, single submitter clinical testing
Personalized Diabetes Medicine Program,University of Maryland School of Medicine RCV001172509 SCV001335562 likely benign Monogenic diabetes 2017-03-31 criteria provided, single submitter research ACMG criteria: BP4 (9 predictors), BP1 (missense when truncating cause disease)=likely benign
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000435494 SCV001797659 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000434450 SCV001931836 benign not specified no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000435494 SCV001975766 likely benign not provided no assertion criteria provided clinical testing
Natera, Inc. RCV001082105 SCV002080408 benign Alstrom syndrome 2019-12-02 no assertion criteria provided clinical testing

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