ClinVar Miner

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

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Total submissions: 7
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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

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