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

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766969	SCV000533001	uncertain significance	not provided	2019-01-08	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ALMS1 gene. The R3632H variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 78/276814 (0.003%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). The R3632H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nonetheless, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
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	2019-12-31	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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.