Submissions for variant NM_001378454.1(ALMS1):c.3307C>G (p.Pro1103Ala)

gnomAD frequency: 0.00038  dbSNP: rs200257398

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534661	SCV000631776	benign	Alstrom syndrome	2025-02-02	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001449720	SCV001652977	benign	not specified	2020-09-04	criteria provided, single submitter	clinical testing	The p.Pro1104Ala variant in ALMS1 is classified as benign because it has been identified in 1.1% (121/10324) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
GeneDx	RCV001549994	SCV001770246	uncertain significance	not provided	2024-09-04	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Ambry Genetics	RCV002323937	SCV002605772	likely benign	Cardiovascular phenotype	2019-01-03	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.
CeGaT Center for Human Genetics Tuebingen	RCV001549994	SCV004698447	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ALMS1: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001449720	SCV005726698	uncertain significance	not specified	2024-11-18	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.3304C>G (p.Pro1102Ala) results in a non-conservative amino acid change located in the Alstrom syndrome repeat domain (IPR040972) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 248472 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00057 vs 0.0022), allowing no conclusion about variant significance. c.3304C>G has been reported in the literature in the heterozygous state in at least one individual affected with Cardiomyopathy who also carried a rare missense variant in ALPK3 (e.g. Burstein_2021) . These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 459864). Based on the evidence outlined above, the variant was classified as uncertain significance.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001549994	SCV001800614	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001549994	SCV001919118	likely benign	not provided		no assertion criteria provided	clinical testing