VCV000203381.47 - ClinVar

NM_001089.3(ABCA3):c.875A>T (p.Glu292Val)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001089.3(ABCA3):c.875A>T (p.Glu292Val)

Variation ID: 203381 Accession: VCV000203381.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16p13.3 16: 2317763 (GRCh38) [ NCBI UCSC ] 16: 2367764 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jul 5, 2015	Jan 25, 2025	Oct 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001089.3:c.875A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001080.2:p.Glu292Val	missense
NC_000016.10:g.2317763T>A
NC_000016.9:g.2367764T>A
NG_011790.1:g.27984A>T

Protein change

E292V

Other names

rs149989682

Canonical SPDI

NC_000016.10:2317762:T:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00080 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00080

Exome Aggregation Consortium (ExAC) 0.00224

The Genome Aggregation Database (gnomAD), exomes 0.00229

The Genome Aggregation Database (gnomAD) 0.00304

Trans-Omics for Precision Medicine (TOPMed) 0.00309

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00331

Links

ClinGen: CA203885 dbSNP: rs149989682 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCA3		-	-	GRCh38 GRCh37	1619	1673

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Interstitial lung disease due to ABCA3 deficiency	Pathogenic/Likely pathogenic (11)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000185556.25
not provided	Pathogenic/Likely pathogenic (6)	criteria provided, multiple submitters, no conflicts	Oct 11, 2024	RCV000224775.30
Pulmonary arterial hypertension Pulmonary valve insufficiency Respiratory insufficiency	Likely pathogenic (1)	criteria provided, single submitter	-	RCV000735281.2
Diffuse interstitial pulmonary fibrosis Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies	Likely pathogenic (1)	criteria provided, single submitter	Aug 13, 2018	RCV000615487.5
Interstitial lung disease 2	Likely pathogenic (1)	criteria provided, single submitter	Aug 1, 2022	RCV002284194.1
Hereditary pulmonary alveolar proteinosis	Pathogenic (1)	criteria provided, single submitter	Apr 1, 2022	RCV002372142.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 19, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281469.2 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pulmonary arterial hypertension Pulmonary valve insufficiency Respiratory insufficiency Affected status: yes Allele origin: germline	Center for Personalized Medicine, Children's Hospital Los Angeles Accession: SCV000854434.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Sex: male
Likely pathogenic (Aug 13, 2018)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Primary interstitial lung disease specific to childhood due to pulmonary surfactant protein anomalies Interstitial lung disease 2 (Autosomal recessive inheritance) Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000711274.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (16) PubMed: 18246475‚ 18317237‚ 18603241‚ 22800827‚ 23166334‚ 17597647‚ 22866751‚ 25553246‚ 18676873‚ 22145626‚ 15976379‚ 24871971‚ 22304854‚ 24136335‚ 22435821‚ 25073622 Comment: The p.Glu292Val variant in ABCA3 has been reported in 22 compound heterozygous a nd 2 homozygous individuals with various respiratory diseases, including idiopat hic pulmonary … (more) The p.Glu292Val variant in ABCA3 has been reported in 22 compound heterozygous a nd 2 homozygous individuals with various respiratory diseases, including idiopat hic pulmonary fibrosis, desquamative interstitial pneumonitis, neonatal respirat ory failure, and childhood interstitial lung disease (Bullard 2005, Shanklin 200 8, Copertino 2012, Epaud 2014, Coghlan 2014, Wambach 2014). A mouse knock-in mod el homozygous for the p.Glu292Val variant displayed phenotypes consistent with i nterstitial lung disease (Tomer 2013). This variant has been identified in 0.43% (543/126312) of European chromosomes, including 3 homozygotes, by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs149989682 ) and is reported in ClinVar (Variation ID: 203381). Please note that for diseas es with recessive inheritance, pathogenic variants may be present at a low frequ ency in the general population. Computational prediction tools and conservation analysis suggest that the p.Glu292Val variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Glu292Val variant is likely pathogenic. ACMG/AMP Criteria applied: P M3_Very Strong; PS3; PP3; BS1_Supporting. (less) Number of individuals with the variant: 2
Likely pathogenic (Jan 24, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: yes Allele origin: germline	AiLife Diagnostics, AiLife Diagnostics Accession: SCV002501179.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022	Publications: PubMed (22) PubMed: 15976379‚ 29566461‚ 22866751‚ 17597647‚ 31589614‚ 30609409‚ 22304854‚ 24136335‚ 18317237‚ 31980526‚ 30755392‚ 22434821‚ 32238781‚ 27516224‚ 18676873‚ 25073622‚ 29431110‚ 33526094‚ 18603241‚ 24871971‚ 27374344‚ 23166334 Number of individuals with the variant: 1 Secondary finding: no
Likely pathogenic (Aug 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Interstitial lung disease 2 Affected status: yes Allele origin: germline	Alder lab, University of Pittsburgh Accession: SCV002573676.1 First in ClinVar: Sep 24, 2022 Last updated: Sep 24, 2022	Number of individuals with the variant: 2 Age: >18 years
Pathogenic (Mar 31, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002767898.1 First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022	Publications: PubMed (6) PubMed: 15976379‚ 18676873‚ 23625987‚ 24871971‚ 25553246‚ 29505158 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pulmonary surfactant metabolism dysfunction 3 (MIM#610921). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (654 heterozygotes, 3 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2 membrane domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common ABCA3 disease-causing variant and has been previously reported in >20 patients with variable respiratory disease including paediatric interstitial lung disease (pILD) and idiopathic pulmonary fibrosis, both in the compound heterozygous and homozygous states (ClinVar, PMID: 15976379, 24871971, 25553246, 23625987). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrate that this variant causes moderately impaired lipid transport of the protein (PMID: 18676873, 29505158). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Likely pathogenic (Mar 08, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV003932190.1 First in ClinVar: Jun 17, 2023 Last updated: Jun 17, 2023	Comment: PS3, PM3, PP3
Likely pathogenic (Sep 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020989.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002273283.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (14) PubMed: 15976379‚ 18317237‚ 23166334‚ 23625987‚ 24871971‚ 29566461‚ 33110422‚ 34715861‚ 35170262‚ 35626240‚ 18676873‚ 22434821‚ 27374344‚ 28034695 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 292 of the ABCA3 protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 292 of the ABCA3 protein (p.Glu292Val). This variant is present in population databases (rs149989682, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive surfactant deficiency and/or pulmonary surfactant metabolism dysfunction. This variant is frequently observed among individuals with ABCA3 deficiency (PMID: 15976379, 18317237, 23166334, 23625987, 24871971, 29566461, 33110422, 34715861, 35170262, 35626240; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203381). 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. Experimental studies have shown that this missense change affects ABCA3 function (PMID: 18676873, 22434821, 27374344, 28034695). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Aug 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004142951.11 First in ClinVar: Nov 20, 2023 Last updated: Dec 22, 2024	Comment: ABCA3: PM2, PM3, PP1, PS3:Supporting Number of individuals with the variant: 1
Likely pathogenic (Oct 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001785976.5 First in ClinVar: Aug 14, 2021 Last updated: Jan 04, 2025	Comment: Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for respiratory distress (PMID: … (more) Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for respiratory distress (PMID: 18317237, 23166334); Published functional studies demonstrate that the variant contributes to loss of epithelial cell differentiation (PMID: 22434821); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29431110, 17597647, 18676873, 18603241, 24136335, 22866751, 30609409, 25553246, 28034695, 27374344, 29505158, 22800827, 22145626, 18246475, 29569581, 29255193, 22304854, 29566461, 31980526, 31589614, 34426522, 34132118, 33526094, 32692933, 32196812, 33359301, 33708521, 23625987, 34662886, 30755392, 18317237, 15976379, 24871971, 22434821, 37657992, 23166334, 27516224, 25073622, 32238781) (less)
Likely pathogenic (Apr 23, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Fulgent Genetics, Fulgent Genetics Accession: SCV005646512.1 First in ClinVar: Jan 25, 2025 Last updated: Jan 25, 2025
Pathogenic (Sep 12, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000345890.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 15976379‚ 18317237 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA3 Number of individuals with the variant: 6 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Feb 04, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV000886879.1 First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018	Publications: PubMed (5) PubMed: 15976379‚ 24871971‚ 29505158‚ 27374344‚ 18676873 Comment: This ABCA3 variant (rs149989682) is present in large population datasets (gnomAD: 660/282370 total alleles; 0.23%; 3 homozygotes). Five submitters in ClinVar classify this variant as … (more) This ABCA3 variant (rs149989682) is present in large population datasets (gnomAD: 660/282370 total alleles; 0.23%; 3 homozygotes). Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant has been reported in numerous affected individuals, both in the compound heterozygous and homozygous state. Multiple functional studies have demonstrated that this variant disrupts ATP hydrolysis and decreases phospholipid transport across the lamellar body membrane. This variant is considered pathogenic. (less)
Pathogenic (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000914713.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (7) PubMed: 18317237‚ 18676873‚ 22866751‚ 22304854‚ 23166334‚ 22434821‚ 15976379 Comment: Across a selection of the available literature the ABCA3 c.875T>A (p.Glu292Val) variant has been reported in a total of 36 patients with various pulmonary disorders, … (more) Across a selection of the available literature the ABCA3 c.875T>A (p.Glu292Val) variant has been reported in a total of 36 patients with various pulmonary disorders, including in ten in a compound heterozygous state with a second missense or intronic variant, and in 26 in a heterozygous state in whom a second variant was not identified (Bullard et al. 2005; Garmany et al. 2008; Copertino et al. 2012; Baekvad-Hansen et al. 2012; Wambach et al. 2012). The variant was reported in three of 638 controls and at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the p.Glu292Val variant exhibits correct cellular localization but moderately impaired transport function, and induces loss of epithelial cell differentiation in lung alveolar epithelia type II cells (Matsumura et al. 2008; Kaltenborn et al. 2011). Based on the collective evidence, the p.Glu292Val variant is classified as pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
Pathogenic (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002517478.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Pathogenic (Apr 01, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary pulmonary alveolar proteinosis Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002686233.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 18676873‚ 23625987‚ 24871971 Comment: The p.E292V pathogenic mutation (also known as c.875A>T), located in coding exon 6 of the ABCA3 gene, results from an A to T substitution at … (more) The p.E292V pathogenic mutation (also known as c.875A>T), located in coding exon 6 of the ABCA3 gene, results from an A to T substitution at nucleotide position 875. The glutamic acid at codon 292 is replaced by valine, an amino acid with dissimilar properties. This is the most common ABCA3 mutation reported to date in pediatric interstitial lung disease and has a carrier rate of 1 in 275 individuals in the United States. In a study with 12 confirmed ABCA3 cases, this mutation was found in the compound heterozygous state in three individuals and in the homozygous state in one individual. Since the four affected individuals were all alive, p.E292V was speculated to be a mild mutation (Turcu S et al. Arch Dis Child. 2013;98(7):490-5). In another study with 185 individuals identified with ABCA3 mutations, this mutation was detected in 16 individuals. One homozygous infant presented with neonatal respiratory failure and died shortly after birth, while the remaining 15 compound heterozygous individuals had variable outcomes (Wambach JA et al. Am J Respir Crit Care Med. 2014;189(12):1538-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Likely pathogenic (Aug 01, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003844892.2 First in ClinVar: Mar 26, 2023 Last updated: Oct 26, 2024	Publications: PubMed (8) PubMed: 23625987‚ 29566461‚ 15976379‚ 22434821‚ 18676873‚ 34132118‚ 27374344‚ 32692933 Comment: Variant summary: ABCA3 c.875A>T (p.Glu292Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more) Variant summary: ABCA3 c.875A>T (p.Glu292Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 250982 control chromosomes, predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA3 causing Pulmonary surfactant metabolism dysfunction phenotype (0.0011). However, c.875A>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with various respiratory diseases, including surfactant deficiency syndrome, respiratory distress syndrome and chronic lung disease (e.g. Bullard_2005, Turcu_2013, Akil_2018, Tomer_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant is a functional hypomorph exhibiting impaired ATPase activity, lipid transport activity, E-cadherin expression and AT2 cell autophagy (Matsumura_2008, Kaltenborn_2012, Wambach_2016, Wambach_2020, Tomer_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23625987, 29566461, 15976379, 22434821, 18676873, 34132118, 27374344, 32692933). ClinVar contains an entry for this variant (Variation ID: 203381). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
Likely pathogenic (Jan 08, 2015)	no assertion criteria provided Method: research	Surfactant metabolism dysfunction, pulmonary, 3 Affected status: no Allele origin: germline	Division of Human Genetics, Children's Hospital of Philadelphia Study: CSER-PediSeq Accession: SCV000238440.1 First in ClinVar: Jul 05, 2015 Last updated: Jul 05, 2015	Publications: PubMed (4) PubMed: 18317237‚ 15976379‚ 22304854‚ 24871971 Comment: The heterozygous variant in the ABCA3 gene (c.875A>T; p.Glu292Val) is considered likely pathogenic. According to Germany et al, the prevalence of this variant is 1:277 … (more) The heterozygous variant in the ABCA3 gene (c.875A>T; p.Glu292Val) is considered likely pathogenic. According to Germany et al, the prevalence of this variant is 1:277 (PMID: 18317237) representing the most common ABCA3 variant associated with childhood interstitial lung disease. This variant has been published as a compound heterozygous variant in multiple affected individuals (PMID: 15976379, 22304854) and as a homozygous variant (PMID: 24871971). This variant represents a non-conservative amino acid change at highly conserved amino acid and nucleotide positions while not being located in a functional domain. In the ExAC database there are 271 alleles out of 121060 tested positive for this change. (less)
Pathogenic (Oct 03, 2018)	no assertion criteria provided Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Clinical Genomics Laboratory, Stanford Medicine Accession: SCV001371857.1 First in ClinVar: Aug 16, 2020 Last updated: Aug 16, 2020	Comment: The p.Glu292Val variant in the ABCA3 gene has been previously reported with a second ABCA3 variant in >20 unrelated individuals with a range of pulmonary … (more) The p.Glu292Val variant in the ABCA3 gene has been previously reported with a second ABCA3 variant in >20 unrelated individuals with a range of pulmonary phenotypes, including respiratory distress, interstitial lung disease, and pulmonary fibrosis, which most commonly presented neonatally or in early childhood (Bullard et al. 2005; Doan et al. 2008; Copertino et al. 2012; Wambach et al. 2012; Turcu et al. 2013; Soares et al. 2013; Epaud et al. 2013; Coghlan et al. 2014; Wambach et al. 2014; KrÃ¶ner et al. 2017; Akil et al. 2018). Compared to frameshift or nonsense pathogenic variants in the ABCA3 gene, the p.Glu292Val variant has been suggested to result in milder disease severity, with many individuals surviving into childhood or adulthood (Bullard et al. 2005; Copertino et al. 2012; Turcu et al. 2013; Epaud et al. 2013). Functional studies of the p.Glu292Val variant consistently demonstrate a deleterious effect and suggest a partial loss of ABCA3 protein activity (Wambach et al. 2016; Matsumura et al. 2018; Schindlbeck et al. 2018). In a large population database, the variant was identified in 543/126312 (0.43%) European chromosomes, including 3 homozygous individuals (Genome Aggregation Database, http://gnomad.broadinstitute.org). This frequency may suggest reduced penetrance of this allele. Additionally, individuals that are heterozygous for the p.Glu292Val variant are reported to have an increased risk for neonatal respiratory distress (Wambach et al. 2012 and Naderi et al. 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu292Val variant as pathogenic for autosomal recessive surfactant metabolism dysfunction, pulmonary, 3. [ACMG evidence codes used: PS3, PS4]. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	Interstitial lung disease due to ABCA3 deficiency Affected status: yes Allele origin: germline	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital Accession: SCV004174106.1 First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023
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Comment:

The p.Glu292Val variant in ABCA3 has been reported in 22 compound heterozygous a nd 2 homozygous individuals with various respiratory diseases, including idiopat hic pulmonary fibrosis, desquamative interstitial pneumonitis, neonatal respirat ory failure, and childhood interstitial lung disease (Bullard 2005, Shanklin 200 8, Copertino 2012, Epaud 2014, Coghlan 2014, Wambach 2014). A mouse knock-in mod el homozygous for the p.Glu292Val variant displayed phenotypes consistent with i nterstitial lung disease (Tomer 2013). This variant has been identified in 0.43% (543/126312) of European chromosomes, including 3 homozygotes, by the Genome Ag gregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs149989682 ) and is reported in ClinVar (Variation ID: 203381). Please note that for diseas es with recessive inheritance, pathogenic variants may be present at a low frequ ency in the general population. Computational prediction tools and conservation analysis suggest that the p.Glu292Val variant may impact the protein, though thi s information is not predictive enough to determine pathogenicity. In summary, a lthough additional studies are required to fully establish its clinical signific ance, the p.Glu292Val variant is likely pathogenic. ACMG/AMP Criteria applied: P M3_Very Strong; PS3; PP3; BS1_Supporting.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pulmonary surfactant metabolism dysfunction 3 (MIM#610921). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to valine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (654 heterozygotes, 3 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC2 membrane domain (PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most common ABCA3 disease-causing variant and has been previously reported in >20 patients with variable respiratory disease including paediatric interstitial lung disease (pILD) and idiopathic pulmonary fibrosis, both in the compound heterozygous and homozygous states (ClinVar, PMID: 15976379, 24871971, 25553246, 23625987). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional studies demonstrate that this variant causes moderately impaired lipid transport of the protein (PMID: 18676873, 29505158). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 292 of the ABCA3 protein (p.Glu292Val). This variant is present in population databases (rs149989682, gnomAD 0.4%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with clinical features of autosomal recessive surfactant deficiency and/or pulmonary surfactant metabolism dysfunction. This variant is frequently observed among individuals with ABCA3 deficiency (PMID: 15976379, 18317237, 23166334, 23625987, 24871971, 29566461, 33110422, 34715861, 35170262, 35626240; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203381). 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. Experimental studies have shown that this missense change affects ABCA3 function (PMID: 18676873, 22434821, 27374344, 28034695). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant found to be over-represented in newborns with respiratory distress syndrome suggesting that E292V or its haplotype impart increased genetic risk for respiratory distress (PMID: 18317237, 23166334); Published functional studies demonstrate that the variant contributes to loss of epithelial cell differentiation (PMID: 22434821); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29431110, 17597647, 18676873, 18603241, 24136335, 22866751, 30609409, 25553246, 28034695, 27374344, 29505158, 22800827, 22145626, 18246475, 29569581, 29255193, 22304854, 29566461, 31980526, 31589614, 34426522, 34132118, 33526094, 32692933, 32196812, 33359301, 33708521, 23625987, 34662886, 30755392, 18317237, 15976379, 24871971, 22434821, 37657992, 23166334, 27516224, 25073622, 32238781)

Comment:

This ABCA3 variant (rs149989682) is present in large population datasets (gnomAD: 660/282370 total alleles; 0.23%; 3 homozygotes). Five submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. This variant has been reported in numerous affected individuals, both in the compound heterozygous and homozygous state. Multiple functional studies have demonstrated that this variant disrupts ATP hydrolysis and decreases phospholipid transport across the lamellar body membrane. This variant is considered pathogenic.

Comment:

Across a selection of the available literature the ABCA3 c.875T>A (p.Glu292Val) variant has been reported in a total of 36 patients with various pulmonary disorders, including in ten in a compound heterozygous state with a second missense or intronic variant, and in 26 in a heterozygous state in whom a second variant was not identified (Bullard et al. 2005; Garmany et al. 2008; Copertino et al. 2012; Baekvad-Hansen et al. 2012; Wambach et al. 2012). The variant was reported in three of 638 controls and at a frequency of 0.00454 in the European American population of the Exome Sequencing Project. Functional studies demonstrated that the p.Glu292Val variant exhibits correct cellular localization but moderately impaired transport function, and induces loss of epithelial cell differentiation in lung alveolar epithelia type II cells (Matsumura et al. 2008; Kaltenborn et al. 2011). Based on the collective evidence, the p.Glu292Val variant is classified as pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

The p.E292V pathogenic mutation (also known as c.875A>T), located in coding exon 6 of the ABCA3 gene, results from an A to T substitution at nucleotide position 875. The glutamic acid at codon 292 is replaced by valine, an amino acid with dissimilar properties. This is the most common ABCA3 mutation reported to date in pediatric interstitial lung disease and has a carrier rate of 1 in 275 individuals in the United States. In a study with 12 confirmed ABCA3 cases, this mutation was found in the compound heterozygous state in three individuals and in the homozygous state in one individual. Since the four affected individuals were all alive, p.E292V was speculated to be a mild mutation (Turcu S et al. Arch Dis Child. 2013;98(7):490-5). In another study with 185 individuals identified with ABCA3 mutations, this mutation was detected in 16 individuals. One homozygous infant presented with neonatal respiratory failure and died shortly after birth, while the remaining 15 compound heterozygous individuals had variable outcomes (Wambach JA et al. Am J Respir Crit Care Med. 2014;189(12):1538-43). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

Variant summary: ABCA3 c.875A>T (p.Glu292Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0023 in 250982 control chromosomes, predominantly at a frequency of 0.0043 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCA3 causing Pulmonary surfactant metabolism dysfunction phenotype (0.0011). However, c.875A>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with various respiratory diseases, including surfactant deficiency syndrome, respiratory distress syndrome and chronic lung disease (e.g. Bullard_2005, Turcu_2013, Akil_2018, Tomer_2021). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant is a functional hypomorph exhibiting impaired ATPase activity, lipid transport activity, E-cadherin expression and AT2 cell autophagy (Matsumura_2008, Kaltenborn_2012, Wambach_2016, Wambach_2020, Tomer_2021). The following publications have been ascertained in the context of this evaluation (PMID: 23625987, 29566461, 15976379, 22434821, 18676873, 34132118, 27374344, 32692933). ClinVar contains an entry for this variant (Variation ID: 203381). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Comment:

The heterozygous variant in the ABCA3 gene (c.875A>T; p.Glu292Val) is considered likely pathogenic. According to Germany et al, the prevalence of this variant is 1:277 (PMID: 18317237) representing the most common ABCA3 variant associated with childhood interstitial lung disease. This variant has been published as a compound heterozygous variant in multiple affected individuals (PMID: 15976379, 22304854) and as a homozygous variant (PMID: 24871971). This variant represents a non-conservative amino acid change at highly conserved amino acid and nucleotide positions while not being located in a functional domain. In the ExAC database there are 271 alleles out of 121060 tested positive for this change.

Comment:

The p.Glu292Val variant in the ABCA3 gene has been previously reported with a second ABCA3 variant in >20 unrelated individuals with a range of pulmonary phenotypes, including respiratory distress, interstitial lung disease, and pulmonary fibrosis, which most commonly presented neonatally or in early childhood (Bullard et al. 2005; Doan et al. 2008; Copertino et al. 2012; Wambach et al. 2012; Turcu et al. 2013; Soares et al. 2013; Epaud et al. 2013; Coghlan et al. 2014; Wambach et al. 2014; KrÃ¶ner et al. 2017; Akil et al. 2018). Compared to frameshift or nonsense pathogenic variants in the ABCA3 gene, the p.Glu292Val variant has been suggested to result in milder disease severity, with many individuals surviving into childhood or adulthood (Bullard et al. 2005; Copertino et al. 2012; Turcu et al. 2013; Epaud et al. 2013). Functional studies of the p.Glu292Val variant consistently demonstrate a deleterious effect and suggest a partial loss of ABCA3 protein activity (Wambach et al. 2016; Matsumura et al. 2018; Schindlbeck et al. 2018). In a large population database, the variant was identified in 543/126312 (0.43%) European chromosomes, including 3 homozygous individuals (Genome Aggregation Database, http://gnomad.broadinstitute.org). This frequency may suggest reduced penetrance of this allele. Additionally, individuals that are heterozygous for the p.Glu292Val variant are reported to have an increased risk for neonatal respiratory distress (Wambach et al. 2012 and Naderi et al. 2014). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Glu292Val variant as pathogenic for autosomal recessive surfactant metabolism dysfunction, pulmonary, 3. [ACMG evidence codes used: PS3, PS4].

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic Challenges in Neonatal Respiratory Distress-Congenital Surfactant Metabolism Dysfunction Caused by ABCA3 Mutation.	Rogulska J	Diagnostics (Basel, Switzerland)	2022	PMID: 35626240
Biologic characterization of ABCA3 variants in lung tissue from infants and children with ABCA3 deficiency.	Xu KK	Pediatric pulmonology	2022	PMID: 35170262
A novel synonymous ABCA3 variant identified in a Chinese family with lethal neonatal respiratory failure.	Zhang W	BMC medical genomics	2021	PMID: 34715861
The common ABCA3(E292V) variant disrupts AT2 cell quality control and increases susceptibility to lung injury and aberrant remodeling.	Tomer Y	American journal of physiology. Lung cellular and molecular physiology	2021	PMID: 34132118
Hydroxychloroquine, a successful treatment for lung disease in ABCA3 deficiency gene mutation: a case report.	Shaaban W	Journal of medical case reports	2021	PMID: 33526094
A Newly Observed Mutation of the ABCA3 Gene Causing Lethal Respiratory Failure of a Full-Term Newborn: A Case Report.	Jouza M	Frontiers in genetics	2020	PMID: 33110422
Functional Genomics of ABCA3 Variants.	Wambach JA	American journal of respiratory cell and molecular biology	2020	PMID: 32692933
ABCA3 mutations in adult pulmonary fibrosis patients: a case series and review of literature.	Klay D	Current opinion in pulmonary medicine	2020	PMID: 32238781
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants.	Ji J	Cold Spring Harbor molecular case studies	2019	PMID: 30755392
Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project.	Ceyhan-Birsoy O	American journal of human genetics	2019	PMID: 30609409
Surfactant deficiency syndrome in an infant with a C-terminal frame shift in ABCA3: A case report.	Akil N	Pediatric pulmonology	2018	PMID: 29566461
ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes.	Schindlbeck U	Human mutation	2018	PMID: 29505158
The Personal Genome Project Canada: findings from whole genome sequences of the inaugural 56 participants.	Reuter MS	CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne	2018	PMID: 29431110
Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene.	Beers MF	Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft	2017	PMID: 28034695
Lung disease caused by ABCA3 mutations.	Kröner C	Thorax	2017	PMID: 27516224
Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome.	Wambach JA	American journal of respiratory cell and molecular biology	2016	PMID: 27374344
Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations.	Coghlan MA	BMJ open respiratory research	2014	PMID: 25553246
Single mutations in ABCA3 increase the risk for neonatal respiratory distress syndrome in late preterm infants (gestational age 34-36 weeks).	Naderi HM	American journal of medical genetics. Part A	2014	PMID: 25073622
Genotype-phenotype correlations for infants and children with ABCA3 deficiency.	Wambach JA	American journal of respiratory and critical care medicine	2014	PMID: 24871971
Combined pulmonary fibrosis and emphysema syndrome associated with ABCA3 mutations.	Epaud R	The European respiratory journal	2014	PMID: 24136335
Genetic testing in children with surfactant dysfunction.	Turcu S	Archives of disease in childhood	2013	PMID: 23625987
Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome.	Wambach JA	Pediatrics	2012	PMID: 23166334
Heterozygosity for E292V in ABCA3, lung function and COPD in 64,000 individuals.	Bækvad-Hansen M	Respiratory research	2012	PMID: 22866751
Polymorphism analysis of the ABCA3 gene: association with neonatal respiratory distress syndrome in preterm infants.	Jiang L	Chinese medical journal	2012	PMID: 22800827
Structural and dynamic aspects of Ca2+ and Mg2+ binding of the regulatory domains of the Na+/Ca2+ exchanger.	Breukels V	Biochemical Society transactions	2012	PMID: 22435821
Respiratory syncytial virus potentiates ABCA3 mutation-induced loss of lung epithelial cell differentiation.	Kaltenborn E	Human molecular genetics	2012	PMID: 22434821
A child with severe pneumomediastinum and ABCA3 gene mutation: a puzzling connection.	Copertino M	Archivos de bronconeumologia	2012	PMID: 22304854
ATP-binding cassette member A3 (E292V) gene mutation and pulmonary morbidity in very-low-birth-weight infants.	Härtel C	Acta paediatrica (Oslo, Norway : 1992)	2012	PMID: 22145626
Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease.	Matsumura Y	American journal of physiology. Lung cellular and molecular physiology	2008	PMID: 18676873
Cerebropulmonary dysgenetic syndrome.	Shanklin DR	Experimental and molecular pathology	2008	PMID: 18603241
Population and disease-based prevalence of the common mutations associated with surfactant deficiency.	Garmany TH	Pediatric research	2008	PMID: 18317237
Haplotype analysis of ABCA3: association with respiratory distress in very premature infants.	Karjalainen MK	Annals of medicine	2008	PMID: 18246475
Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation.	Bullard JE	Pediatric research	2007	PMID: 17597647
ABCA3 mutations associated with pediatric interstitial lung disease.	Bullard JE	American journal of respiratory and critical care medicine	2005	PMID: 15976379
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=ABCA3	-	-	-	-
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Text-mined citations for rs149989682 ...

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Record last updated Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_001089.3(ABCA3):c.875A>T (p.Glu292Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149989682 ...