Submissions for variant NM_001378454.1(ALMS1):c.9389C>G (p.Pro3130Arg)

gnomAD frequency: 0.00017  dbSNP: rs200586877

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445473	SCV000536986	likely benign	Monogenic diabetes	2019-01-25	criteria provided, single submitter	research	ACMG criteria: BP4 (REVEL 0.037 + 7 predictors), BP1 (missense variant when truncating case disease)=likely benign
Phosphorus, Inc.	RCV000577939	SCV000679929	uncertain significance	Alstrom syndrome	2017-08-01	criteria provided, single submitter	clinical testing
Invitae	RCV000577939	SCV000832537	uncertain significance	Alstrom syndrome	2022-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 3131 of the ALMS1 protein (p.Pro3131Arg). This variant is present in population databases (rs200586877, gnomAD 0.03%). 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: 393378). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193867	SCV001363020	uncertain significance	not specified	2019-02-25	criteria provided, single submitter	clinical testing	Variant summary: The variant, ALMS1 c.9386C>G (p.Pro3129Arg, also known as c.9392C>G) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 277096 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00016 vs 0.0022), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9386C>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Uncertain Significance X2 ; Likely benign X1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001193867	SCV001365712	uncertain significance	not specified	2020-01-24	criteria provided, single submitter	clinical testing	The p.Pro3131Arg variant in ALMS1 has not been previously reported in individuals with hearing loss, but has been identified in 0.03% (46/128626) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 393378). Computational prediction tools and conservation analysis suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, BP4.
GeneDx	RCV001552478	SCV001773167	uncertain significance	not provided	2022-12-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002374731	SCV002686399	likely benign	Cardiovascular phenotype	2022-08-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000577939	SCV003928173	uncertain risk allele	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 rs200586877 in Alstrom syndrome yet.
Natera, Inc.	RCV000577939	SCV001453033	uncertain significance	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing