Submissions for variant NM_001378454.1(ALMS1):c.4405C>A (p.Pro1469Thr)

gnomAD frequency: 0.00006  dbSNP: rs373638043

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445538	SCV000536970	uncertain significance	Monogenic diabetes	2015-08-07	criteria provided, single submitter	research	ACMG Criteria: PP3, BP4
Counsyl	RCV000666784	SCV000791138	uncertain significance	Alstrom syndrome	2017-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201200	SCV001372275	uncertain significance	not specified	2020-06-29	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.4402C>A (p.Pro1468Thr, also known as c.4408C>A, p.P1470T) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249216 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (4.4e-05 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.4402C>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. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001575003	SCV001801911	uncertain significance	not provided	2021-05-10	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae	RCV000666784	SCV002273265	uncertain significance	Alstrom syndrome	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1470 of the ALMS1 protein (p.Pro1470Thr). This variant is present in population databases (rs373638043, gnomAD 0.01%). 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: 393373). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002329006	SCV002627881	uncertain significance	Cardiovascular phenotype	2020-07-29	criteria provided, single submitter	clinical testing	The p.P1470T variant (also known as c.4408C>A), located in coding exon 8 of the ALMS1 gene, results from a C to A substitution at nucleotide position 4408. The proline at codon 1470 is replaced by threonine, an amino acid with highly 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.
Fulgent Genetics, Fulgent Genetics	RCV000666784	SCV002794009	uncertain significance	Alstrom syndrome	2022-03-11	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000666784	SCV003928143	uncertain significance	Alstrom syndrome		criteria provided, single submitter	research	Potent mutations in ALMS1 are associated with a rare condition called Alstrom syndrome. It can cause excessive eating, insulin resistance. However, no evidence is found to ascertain the role of rs373638043 in Alstrom syndrome yet.
Natera, Inc.	RCV000666784	SCV002080506	uncertain significance	Alstrom syndrome	2021-03-12	no assertion criteria provided	clinical testing
GenomeConnect - Brain Gene Registry	RCV000666784	SCV002760020	not provided	Alstrom syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 01-29-2021 by Lab or GTR ID Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator John Constantino MD PhD from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.