Submissions for variant NM_001378454.1(ALMS1):c.6302C>G (p.Ser2101Trp)

dbSNP: rs28730854

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001698278	SCV000531745	likely benign	not provided	2020-08-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25846608)
Invitae	RCV000865671	SCV001006674	likely benign	Alstrom syndrome	2024-01-16	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001172506	SCV001335559	benign	Monogenic diabetes	2017-10-06	criteria provided, single submitter	research	ACMG criteria: BP4 (4 predictors), PP3 (2 predictors), BS1 (4.97% in European in 1000g), BS2 (61 homozygotes in ExAC), BP1 (missense in gene with truncating known) = benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000439863	SCV001339093	uncertain significance	not specified	2020-03-16	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.6299C>G (p.Ser2100Trp; also known as legacy name c. 6305C>G; p.Ser2102Trp) 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 0.00029 in 247674 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (0.00029 vs 0.0022), allowing no conclusion about variant significance. c.6299C>G has been reported in the literature in at least one individual affected with Alstrom Syndrome (Marshall_2015). This report does 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory cited the variant as likely benign, and one laboratory cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002365550	SCV002660576	likely benign	Cardiovascular phenotype	2022-08-29	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.