Submissions for variant NM_001378454.1(ALMS1):c.2309C>T (p.Pro770Leu)

gnomAD frequency: 0.00011  dbSNP: rs187132771

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000669480	SCV000794237	uncertain significance	Alstrom syndrome	2017-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175437	SCV001338988	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.2306C>T (p.Pro769Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 248720 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2306C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001564982	SCV001788234	uncertain significance	not provided	2024-08-19	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000669480	SCV002130547	uncertain significance	Alstrom syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 771 of the ALMS1 protein (p.Pro771Leu). This variant is present in population databases (rs187132771, gnomAD 0.05%). 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: 553937). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002442398	SCV002735346	likely benign	Cardiovascular phenotype	2024-05-16	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.
Natera, Inc.	RCV000669480	SCV002080453	uncertain significance	Alstrom syndrome	2021-05-04	no assertion criteria provided	clinical testing