Submissions for variant NM_001089.3(ABCA3):c.1474dup (p.Tyr492fs)

gnomAD frequency: 0.00002  dbSNP: rs756855585

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008382	SCV001168150	likely pathogenic	not provided	2018-09-25	criteria provided, single submitter	clinical testing	The c.1474dupT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is observed in 2/9850 (0.0203%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). It causes a frameshift starting with codon Tyrosine 492, changes this amino acid to a Leucine residue and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Tyr492LeufsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we consider this variant to be likely pathogenic.
Ambry Genetics	RCV002391074	SCV002697042	pathogenic	Hereditary pulmonary alveolar proteinosis	2016-03-16	criteria provided, single submitter	clinical testing	The c.1474dupT pathogenic mutation, located in coding exon 10 of the ABCA3 gene, results from a duplication of T at nucleotide position 1474, causing a translational frameshift with a predicted alternate stop codon. This mutation was detected in three siblings who were homozygous for this mutation and had severe lung disease (Wambach JA, Am. J. Respir. Crit. Care Med. 2014 Jun; 189(12):1538-43). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
Invitae	RCV001008382	SCV004539018	pathogenic	not provided	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr492Leufs*18) in the ABCA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA3 are known to be pathogenic (PMID: 27516224). This variant is present in population databases (rs756855585, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with autosomal recessive ABCA3-related conditions (PMID: 24871971). This variant is also known as c.1474_1475insT. ClinVar contains an entry for this variant (Variation ID: 817265). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987759	SCV004803249	pathogenic	Interstitial lung disease due to ABCA3 deficiency	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: ABCA3 c.1474dupT (p.Tyr492LeufsX18) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251380 control chromosomes. c.1474dupT has been reported in the literature in at least one individual affected with Pulmonary surfactant metabolism dysfunction (e.g., Wambach_2014). The following publication have been ascertained in the context of this evaluation (PMID: 24871971). ClinVar contains an entry for this variant (Variation ID: 817265). Based on the evidence outlined above, the variant was classified as pathogenic.