Submissions for variant NM_001378454.1(ALMS1):c.4400G>T (p.Gly1467Val)

gnomAD frequency: 0.00071  dbSNP: rs78102263

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088077	SCV000290088	likely benign	Alstrom syndrome	2024-01-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000520376	SCV000620230	uncertain significance	not provided	2024-06-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172521	SCV001335574	likely benign	Monogenic diabetes	2018-12-07	criteria provided, single submitter	research	ACMG criteria: BP4 (REVEL 0.031 + 6 predictors; not using PP3/3 predictors) + BP1 (truncating cause disease) = likely benign
Genetic Services Laboratory, University of Chicago	RCV001820749	SCV002066331	likely benign	not specified	2021-07-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002327141	SCV002631861	likely benign	Cardiovascular phenotype	2021-05-18	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	RCV001088077	SCV003928167	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 rs78102263 in Alstrom syndrome yet.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001820749	SCV004029123	likely benign	not specified	2023-07-24	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.4397G>T (p.Gly1466Val) results in a non-conservative amino acid change in 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 0.0002 in 249198 control chromosomes, predominantly at a frequency of 0.0032 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variat as likely benign (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Natera, Inc.	RCV001088077	SCV001453455	likely benign	Alstrom syndrome	2020-01-10	no assertion criteria provided	clinical testing