Submissions for variant NM_001378454.1(ALMS1):c.11407C>T (p.Pro3803Ser)

gnomAD frequency: 0.00097  dbSNP: rs189032342

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000471192	SCV000554315	likely benign	Alstrom syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172498	SCV001335551	likely benign	Monogenic diabetes	2018-12-21	criteria provided, single submitter	research	ACMG criteria: BP1 + BS1 (0.3% MAF in gnomAD Africans) = likely benign (REVEL 0.161 + PP3/5 predictors + BP4/4 predictors = conflicting evidence, not using)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260369	SCV001437317	likely benign	not specified	2022-09-26	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.11404C>T (p.Pro3802Ser) (also referred to as c.11410C>T in RefSeq, p.Pro3804Ser) results in a non-conservative amino acid change located in the Alstrom syndrome protein 1 domain (IPR028781) 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 0.00024 in 248974 control chromosomes, predominantly at a frequency of 0.0033 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 predicted 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. To our knowledge, no occurrence of c.11404C>T in individuals affected with Alstrom Syndrome With Dilated 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 and classified the variant as likely benign (n=2) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx	RCV001573772	SCV001875181	uncertain significance	not provided	2022-08-19	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; This variant is associated with the following publications: (PMID: 26582918)
Ambry Genetics	RCV002451150	SCV002614488	likely benign	Cardiovascular phenotype	2021-03-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV000471192	SCV003928176	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 rs189032342 in Alstrom syndrome yet.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001573772	SCV001800121	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001573772	SCV001924325	likely benign	not provided		no assertion criteria provided	clinical testing