Submissions for variant NM_001089.3(ABCA3):c.2309C>T (p.Pro770Leu)

gnomAD frequency: 0.00242  dbSNP: rs143929832

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000345051	SCV000395994	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000732937	SCV000520874	uncertain significance	not provided	2018-03-13	criteria provided, single submitter	clinical testing	The P770L variant in the ABCA3 gene has been previously reported as a single heterozygous variant in an infant with interstitial lung disease; a second variant in ABCA3, as would be expected with autosomal recessive ABCA3-related lung disease, was not identified and further evidence supporting the pathogenicity of this variant was not specified (Griese et al., 2015). Although not present in the homozygous state, the NHLBI ESP Exome Sequencing Project reports P770L was observed in 16/8600 (0.19%) alleles from individuals of European American background, indicating it may be a rare variant in this population. The P770L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P770L as a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000732937	SCV000860938	uncertain significance	not provided	2018-05-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000732937	SCV001048963	likely benign	not provided	2024-12-19	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000345051	SCV001478416	uncertain significance	Interstitial lung disease due to ABCA3 deficiency	2021-01-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002429269	SCV002731807	likely benign	Hereditary pulmonary alveolar proteinosis	2021-05-13	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.