Submissions for variant NM_001378454.1(ALMS1):c.10238A>G (p.Glu3413Gly)

gnomAD frequency: 0.00032  dbSNP: rs184779459

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000544449	SCV000631751	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000544449	SCV000788975	uncertain significance	Alstrom syndrome	2016-12-23	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000413690	SCV001365663	likely benign	not specified	2017-08-23	criteria provided, single submitter	clinical testing	p.Glu3412Gly in exon 15 of ALMS1: This variant is not expected to have clinical significance because it has been identified in 0.49% (42/8554) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs184779459).
Pars Genome Lab	RCV000544449	SCV001736842	likely benign	Alstrom syndrome	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001569636	SCV001793755	likely benign	not provided	2020-10-13	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26047050)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000413690	SCV002548522	likely benign	not specified	2022-05-11	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.10235A>G (p.Glu3412Gly, also known as c.10241A>G in RefSeq) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00052 in 249224 control chromosomes, predominantly at a frequency of 0.0065 within the East Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome phenotype (0.0014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=4, VUS n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002379273	SCV002695321	benign	Cardiovascular phenotype	2023-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000413690	SCV000492122	uncertain significance	not specified	2016-11-30	flagged submission	clinical testing	One individual with Leber congenital amaurosis (LCA) has been reported to be homozygous for the E3414G variant (published using alternative nomenclature E3412G) in the ALMS1 gene, though neither deletion analysis of the ALMS1 gene nor parental consanguinity status or genotypes were reported (Wang et al., 2015). Furthermore, this individual was also apparently homozygous for a truncating variant in the LCA5 gene, which would better explain a typical LCA phenotype. The E3414G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Though E3414G variant was not observed with any significant frequency in over 80,000 individuals of European and African ancestry in the Exome Aggregation Consortium, it was reported in 42/8554 (0.5%) alleles in individuals of East Asian background. Additionally, this substitution occurs at a position that is not conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Lastly, while some missense variants have been reported in association with Alstrom syndrome, most pathogenic variants in ALMS1 reported to date introduce a premature termination codon (Marshall et al., 2012; Stenson et al., 2014).