Submissions for variant NM_001378454.1(ALMS1):c.671C>A (p.Pro224His)

gnomAD frequency: 0.01714  dbSNP: rs11889925

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082986	SCV000262085	benign	Alstrom syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224355	SCV000280857	benign	not provided	2015-06-04	criteria provided, single submitter	clinical testing
GeneDx	RCV000424132	SCV000532582	benign	not specified	2016-10-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445509	SCV000536961	benign	Monogenic diabetes	2019-02-08	criteria provided, single submitter	research	ACMG criteria: BA1 (5.6% in gnomAD African), BS2 (46 homozygotes in gnomAD), BP1 (most ALMS1 pathogenic variants are truncating) REVEL score 0.2 + PP3 (4 predictors) + BP4 (5 predictors)= conflicting evidence, not using)= benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000424132	SCV000864084	benign	not specified	2016-02-15	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.671C>A (alternative name c.674C>A) affects a conserved nucleotide, resulting in amino acid change from Pro to His. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index), however, these predictions have not been validated through in vitro/vivo functional studies yet. This variant was found in 658/122504 control chromosomes from ExAC dataset at a frequency of 0.0053713, predominantly in individuals of African descent (0.05675) including 18 homozygotes. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0022361), suggesting this variant is benign ethnic-specific polymorphism. This variant, to our knowledge, has not been reported in affected individuals via publications. One clinical laboratory (via ClinVar) classified this variant as benign, without evidence to independently evaluate. Taken together, this variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000424132	SCV000967040	benign	not specified	2016-03-21	criteria provided, single submitter	clinical testing	p.Pro224His in exon 4 of ALMS1: This variant is not expected to have clinical si gnificance because it has been identified in 5.67% (556/9798) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs11889925).
Athena Diagnostics Inc	RCV000224355	SCV001143005	benign	not provided	2019-03-21	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001082986	SCV002605237	likely risk allele	Alstrom syndrome	2024-02-15	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 rs11889925 in Alstrom syndrome yet.This variant is a potent moderate impact, deleterious variant with a CADD score of 25.2. This gene is found to be frequently associated with Alstrom syndrome as per recent evidence as well, with sufficient scientific evidence to support the reported classification.
Ambry Genetics	RCV002363032	SCV002663606	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001082986	SCV004563999	benign	Alstrom syndrome	2023-09-06	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001082986	SCV001457869	benign	Alstrom syndrome	2020-09-16	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224355	SCV001799888	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000424132	SCV001929735	benign	not specified		no assertion criteria provided	clinical testing