Submissions for variant NM_001378454.1(ALMS1):c.3103C>T (p.Pro1035Ser)

gnomAD frequency: 0.00010  dbSNP: rs531648685

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000431219	SCV000532159	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001242965	SCV001416091	uncertain significance	Alstrom syndrome	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1036 of the ALMS1 protein (p.Pro1036Ser). This variant is present in population databases (rs531648685, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 389575). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251290	SCV001426826	uncertain significance	not specified	2021-04-26	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.3100C>T (p.Pro1034Ser) results in a non-conservative amino acid change located in the Alstrom syndrome repeat (IPR040972) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 248852 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ALMS1 causing Alstrom Syndrome With Dilated Cardiomyopathy (8e-05 vs 0.0018), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3100C>T in individuals affected with Alstrom Syndrome With Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with other pathogenic variant has been reported internally (LMNA c.949G>A, p.Glu317Lys), providing supporting evidence for a benign role. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002323644	SCV002605938	likely benign	Cardiovascular phenotype	2024-05-17	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.
Fulgent Genetics, Fulgent Genetics	RCV001242965	SCV002786259	uncertain significance	Alstrom syndrome	2022-04-25	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001242965	SCV002080475	uncertain significance	Alstrom syndrome	2021-09-15	no assertion criteria provided	clinical testing