ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.11798G>A (p.Arg3933His)

gnomAD frequency: 0.00003  dbSNP: rs45576434
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668429 SCV000793028 uncertain significance Alstrom syndrome 2017-07-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000735891 SCV000864122 uncertain significance not specified 2017-01-03 criteria provided, single submitter clinical testing Variant summary: The ALMS1 c.11795G>A (p.Arg3932His, alternative name c.11801G>A) variant involves the alteration of a non-conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/120564 (1/30120), which does not exceed the estimated maximal expected allele frequency for a pathogenic ALMS1 variant of 1/447. A publication cites the variant to have been found in a cohort of Alstrom syndrome patients, however, co-occurrence and cosegregation data was not provided. The variant of interest has not been reported by clinical diagnostic laboratories or databases, to our knowledge. Therefore, due to the limited available information (ie, lack of clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Ambry Genetics RCV002331306 SCV002633470 uncertain significance Cardiovascular phenotype 2020-03-13 criteria provided, single submitter clinical testing The p.R3934H variant (also known as c.11801G>A), located in coding exon 18 of the ALMS1 gene, results from a G to A substitution at nucleotide position 11801. The arginine at codon 3934 is replaced by histidine, an amino acid with highly similar properties. This variant was identified in two individuals with Alstrom syndrome; however, additional details were not provided (Marshall JD et al. Hum. Mutat., 2007 Nov;28:1114-23). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000668429 SCV003272517 uncertain significance Alstrom syndrome 2022-08-03 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3934 of the ALMS1 protein (p.Arg3934His). This variant is present in population databases (rs45576434, gnomAD 0.005%). This missense change has been observed in individual(s) with Alstrom syndrome (PMID: 17594715). ClinVar contains an entry for this variant (Variation ID: 553055). 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.
Natera, Inc. RCV000668429 SCV002079032 uncertain significance Alstrom syndrome 2021-09-10 no assertion criteria provided clinical testing

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