ClinVar Miner

Submissions for variant NM_001378454.1(ALMS1):c.9359A>C (p.Lys3120Thr) (rs375038066)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669960 SCV000794763 uncertain significance Alstrom syndrome 2017-10-16 criteria provided, single submitter clinical testing
Invitae RCV000669960 SCV001202571 uncertain significance Alstrom syndrome 2020-03-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 3121 of the ALMS1 protein (p.Lys3121Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs375038066, ExAC 0.03%). This variant has not been reported in the literature in individuals with ALMS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 554344). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Not Available; Align-GVGD: Class C0). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356778 SCV001552038 uncertain significance not provided no assertion criteria provided clinical testing The ALMS1 p.K3119T variant was not identified in the literature but was identified in dbSNP (ID: rs375038066) and ClinVar (classified as uncertain significance by Counsyl and Invitae). The variant was identified in control databases in 7 of 280884 chromosomes at a frequency of 0.00002492 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.K3119 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, MutationTaster, Revel, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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