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

gnomAD frequency: 0.00285  dbSNP: rs45630557

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082105	SCV000290072	benign	Alstrom syndrome	2024-01-31	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	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	2024-07-01	criteria provided, single submitter	clinical testing	ALMS1: BP4, BS2
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
Ambry Genetics	RCV002374373	SCV002687980	likely benign	Cardiovascular phenotype	2019-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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