Submissions for variant NM_001378454.1(ALMS1):c.6082T>C (p.Ser2028Pro)

gnomAD frequency: 0.00163  dbSNP: rs149096794

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001580495	SCV000535171	likely benign	not provided	2021-08-05	criteria provided, single submitter	clinical testing
Invitae	RCV000468666	SCV000554292	likely benign	Alstrom syndrome	2024-01-28	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172526	SCV001335579	likely benign	Monogenic diabetes	2017-02-17	criteria provided, single submitter	research	ACMG criteria: PP3 (3 predictors), BS1 (1% in 1000G-AFR), BP4 (4 predictors), BP1 (truncating known to cause disease), (BS2)for 1 homozygote in ExAC=Likely Benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000436669	SCV001363240	benign	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.6079T>C, also referred to as c.6085T>C using the refseq HGVS naming convention (p.Ser2027Pro), results in a non-conservative amino acid change located in the Alstrom syndrome repeat domain (IPR040972) of 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 0.00039 in 249198 control chromosomes, predominantly at a frequency of 0.0055 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Cardiomyopathy phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.6079T>C 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. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000468666	SCV002605258	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 rs149096794 in Alstrom syndrome yet.
Ambry Genetics	RCV002356622	SCV002657761	benign	Cardiovascular phenotype	2019-01-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Fulgent Genetics, Fulgent Genetics	RCV000468666	SCV002807321	likely benign	Alstrom syndrome	2021-11-15	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000468666	SCV003919971	uncertain significance	Alstrom syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ALMS1 NM_015120.4 exon 8 p.Ser2027Pro (c.6079T>C): This variant has not been reported in the literature but is present in 0.5% (129/24192) of African alleles in the Genome Aggregation Database, including one homozygote (https://gnomad.broadinstitute.org/variant/2-73679736-T-C). This variant is present in ClinVar (Variation ID:391989). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.