Submissions for variant NM_001378454.1(ALMS1):c.8359A>G (p.Ile2787Val)

gnomAD frequency: 0.00036  dbSNP: rs200075429

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000595220	SCV000705442	uncertain significance	not provided	2017-02-15	criteria provided, single submitter	clinical testing
Invitae	RCV000794425	SCV000933830	uncertain significance	Alstrom syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2788 of the ALMS1 protein (p.Ile2788Val). This variant is present in population databases (rs200075429, gnomAD 0.1%). This missense change has been observed in individual(s) with clinical features of ALMS1-related disease (PMID: 25468891). This variant is also known as c.8356A>G, p.Ile2786Val. ClinVar contains an entry for this variant (Variation ID: 499776). 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	RCV001175497	SCV001339095	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: ALMS1 c.8356A>G (p.Ile2786Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.7e-05 in 247260 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ALMS1 causing Cardiomyopathy (5.7e-05 vs 0.0022), allowing no conclusion about variant significance. c.8356A>G has been reported in the literature in one individual affected with Usher syndrome type I (Bujakowska_2014). The report does not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no occurrence of c.8356A>G in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. 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.
GeneDx	RCV000595220	SCV001802957	uncertain significance	not provided	2023-11-06	criteria provided, single submitter	clinical testing	Reported in the presence of two other ALMS1 variants, phase unknown, in a patient of Puerto Rican background with congenital hearing loss, retinitis pigmentosa, delalyed walking, and a clinical diagnosis of Usher syndrome type I (PMID: 25468891); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as p.(I2786V); This variant is associated with the following publications: (PMID: 25468891)
Ambry Genetics	RCV002438538	SCV002676659	likely benign	Cardiovascular phenotype	2021-05-14	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.
Fulgent Genetics, Fulgent Genetics	RCV000794425	SCV002792236	uncertain significance	Alstrom syndrome	2022-03-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000794425	SCV002082904	uncertain significance	Alstrom syndrome	2021-05-04	no assertion criteria provided	clinical testing