ClinVar Miner

Submissions for variant NM_130847.3(AMOTL1):c.479C>T (p.Pro160Leu)

dbSNP: rs1951433087
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Hadassah Hebrew University Medical Center RCV001254927 SCV001364376 likely pathogenic Hypertelorism; Cleft lip/palate; Abnormal pinna morphology; Tethered cord; Long fingers; imperforate anus with fistula 2019-06-20 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001863069 SCV002252531 pathogenic not provided 2023-07-08 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with clinical features of AMOTL1-related conditions (PMID: 33026150, 36751037; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 160 of the AMOTL1 protein (p.Pro160Leu). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 929484).
GeneDx RCV001863069 SCV003805326 uncertain significance not provided 2022-11-30 criteria provided, single submitter clinical testing De novo variant with confirmed parentage in a patient with cleft lip and palate, imperforate anus, and dysmorphic features in the published literature (Rips et al., 2021); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 33026150)
Ambry Genetics RCV004935189 SCV005612642 pathogenic not specified 2024-09-13 criteria provided, single submitter clinical testing The c.479C>T (p.P160L) alteration is located in exon 3 (coding exon 3) of the AMOTL1 gene. This alteration results from a C to T substitution at nucleotide position 479, causing the proline (P) at amino acid position 160 to be replaced by a leucine (L). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been determined to be the result of a de novo mutation in multiple individuals with features consistent with AMOTL1-related orofacial clefts (Rips, 2021; Strong, 2023). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

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