Submissions for variant NM_001378454.1(ALMS1):c.10892G>A (p.Arg3631His) (rs142558799)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766969	SCV000533001	uncertain significance	not provided	2021-07-15	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported in ClinVar with conflicting classifications ranging from likely benign to variant of uncertain significance (ClinVar Variant ID# 390222; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 27535533, 26582918)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000431898	SCV000713800	uncertain significance	not specified	2017-12-21	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg3632His va riant in ALMS1 gene has not been previously reported in individuals with hearing loss or Alstrom syndrome, but has been identified in several populations by the Genome Aggregation Database with the highest frequency of 0.21%(51/24014) of Af rican chromosomes (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs142558799). This variant has also been reported in an affected individual of unspecified ph enotypes in ClinVar (Variation ID: 390222). Computational prediction tools and c onservation analysis do not provide strong support for or against an impact to t he protein. In summary, while the clinical significance of the p.Arg3630His vari ant is uncertain, the frequency data indicate that it is more likely to be benig n. ACMG/AMP criteria applied: BS1_supporting.
Invitae	RCV001086177	SCV000756144	likely benign	Alstrom syndrome	2020-11-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000431898	SCV000864101	uncertain significance	not specified	2018-05-29	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.10889G>A (p.Arg3630His, alternative name c.10895G>A) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 276814 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00028 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.10889G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc.	RCV001086177	SCV001459599	likely benign	Alstrom syndrome	2020-06-05	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000766969	SCV001798036	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000766969	SCV001967530	uncertain significance	not provided		no assertion criteria provided	clinical testing