Submissions for variant NM_001378454.1(ALMS1):c.12044G>A (p.Gly4015Asp)

gnomAD frequency: 0.00022  dbSNP: rs200462734

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413866	SCV000491842	uncertain significance	not specified	2016-11-23	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the ALMS1 gene. The G4016D variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. This substitution occurs at a position that is not conserved across species. In silico analysis predicts this variant likely does not alter the protein structure/function. Nevertheless, the G4016D 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.
Invitae	RCV000477216	SCV000541334	uncertain significance	Alstrom syndrome	2022-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 4016 of the ALMS1 protein (p.Gly4016Asp). This variant is present in population databases (rs200462734, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 373262). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Athena Diagnostics Inc	RCV000991516	SCV001142997	uncertain significance	not provided	2019-08-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002348131	SCV002649985	uncertain significance	Cardiovascular phenotype	2023-04-04	criteria provided, single submitter	clinical testing	The p.G4016D variant (also known as c.12047G>A), located in coding exon 19 of the ALMS1 gene, results from a G to A substitution at nucleotide position 12047. The glycine at codon 4016 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000991516	SCV001553166	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ALMS1 p.Gly4014Asp variant was not identified in the literature but was identified in dbSNP (ID: rs200462734) and ClinVar (uncertain significance by GeneDx and Invitae). The variant was identified in control databases in 60 of 281608 chromosomes at a frequency of 0.0002131 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 50 of 128624 chromosomes (freq: 0.000389), Other in 2 of 7164 chromosomes (freq: 0.000279), African in 2 of 24396 chromosomes (freq: 0.000082), European (Finnish) in 2 of 25106 chromosomes (freq: 0.00008), South Asian in 2 of 30616 chromosomes (freq: 0.000065) and Latino in 2 of 35430 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Gly4014 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Natera, Inc.	RCV000477216	SCV002079046	uncertain significance	Alstrom syndrome	2021-07-27	no assertion criteria provided	clinical testing