rs201299260

Positions:

• chr16-2319616-G-A
• chr16-2319616-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001089.3(ABCA3):​c.838C>T​(p.Arg280Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,613,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: ABCA3 NM_001089.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: 9.62

Genes affected

ABCA3 (HGNC:33): (ATP binding cassette subfamily A member 3) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intracellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the ABC1 subfamily. Members of the ABC1 subfamily comprise the only major ABC subfamily found exclusively in multicellular eukaryotes. The full transporter encoded by this gene may be involved in development of resistance to xenobiotics and engulfment during programmed cell death. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924
• PP5: Variant 16-2319616-G-A is Pathogenic according to our data. Variant chr16-2319616-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 318566.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=5, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCA3	NM_001089.3	c.838C>T	p.Arg280Cys	missense_variant	8/33	ENST00000301732.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCA3	ENST00000301732.10	c.838C>T	p.Arg280Cys	missense_variant	8/33	1	NM_001089.3	P1
ABCA3	ENST00000382381.7	c.838C>T	p.Arg280Cys	missense_variant	8/32	1
ABCA3	ENST00000563623.5	n.1401C>T		non_coding_transcript_exon_variant	8/20	1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152120 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000172 AC: 43 AN: 250570 Hom.: 0 AF XY: 0.000192 AC XY: 26 AN XY: 135430

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 338 AN: 1461024 Hom.: 0 Cov.: 35 AF XY: 0.000226 AC XY: 164 AN XY: 726748

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000281

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152120 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74314

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000983

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000183 Hom.: 1

Bravo AF: 0.000212

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Interstitial lung disease due to ABCA3 deficiency Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ABCA3 c.838C>T (p.Arg280Cys) missense variant has been reported three studies in which it is found in three patients in a compound heterozygous state including in one child with interstitial lung disease secondary to ABCA3 deficiency in a compound heterozygous state with a second missense variant, in one infant with unexplained respiratory distress, in whom a second variant could not be identified and in a third patient with pulmonary surfactant deficiency, in cis with a stop-gained variant and in trans with a synonymous variant (Somaschini et al. 2007; Williamson et al. 2014; Jackson et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00024 in the European (non-Finnish) population of the Exome Aggregation Consortium. Weichert et al. (2011) demonstrated that human alveolar epithelial A549 cells expressing the p.Arg280Cys variant partially impaired transport of the ABCA3 protein through the endoplasmic reticulum (ER) leading to retention in the ER compared to wild type. Based on the evidence, the p.Arg280Cys variant is classified likely pathogenic for pulmonary surfactant metabolism dysfunction. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with surfactant metabolism dysfunction, pulmonary, 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 arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (45 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2 & v3) (highest allele count: 231 heterozygotes, 1 homozygote). (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 ABC-2 family transporter protein domain (DECIPHER) (I) 0708 - Another missense variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. p.(Arg280His) has been classified as a VUS by multiple clinical laboratories in ClinVar, and as likely benign by one. This variant has also been observed as heterozygous in an individual with idiopathic interstitial pneumonia, and with a second ABCA3 variant in an individual with lung disease (phase unknown) (PMIDs: 20656946, 27516224). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as pathogenic, likely pathogenic and as a VUS by clinical laboratories in ClinVar. This variant has been observed in two individuals with interstitial lung disease who also had a second ABCA3 variant (one compound heterozygous, the other phase unknown) (PMIDs: 23625987, 24115460, 36370864). However, this variant has also been observed in cis with a nonsense variant p.(Gln1589*) in three individuals with respiratory failure, once as a homozygous allele, once in trans with another ABCA3 missense variant, and once as heterozygous (PMIDs: 25712598, 24871971). (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. This variant has been shown to be partially retained in the endoplasmic reticulum, leading to ER stress and apoptosis (PMID: 21214890). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 06, 2019	This ABCA3 variant (rs201299260) is rare (<0.1%) in a large population dataset (gnomAD: 45/281924 total alleles; 0.016%; no homozygotes). Two submitters in ClinVar classify c.838C>T as a variant of uncertain clinical significance. This variant has been reported in numerous patients with respiratory distress. A functional study has demonstrated that this variant affects normal ABCA3 protein trafficking and folding. This variant is considered pathogenic. -

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 21, 2019	This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 25712598, 24115460, 17517255, 22337229). Assessment of experimental evidence suggests this variant results in abnormal protein function (PMID: 21214890). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 280 of the ABCA3 protein (p.Arg280Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with autosomal recessive interstitial lung disease (PMID: 17517255, 24115460, 24871971, 32238781). ClinVar contains an entry for this variant (Variation ID: 318566). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCA3 protein function. Experimental studies have shown that this missense change affects ABCA3 function (PMID: 21214890). 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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 05, 2018	The p.Arg280Cys variant in ABCA3 has been reported in the compound heterozygous state in 1 individual with interstitial lung disease (ILD) and has also been rep orted in cis with the p.Q1589X variant in ABCA3 in 2 individuals with ILD who c arried another variant in trans (Williamson 2014, Wambach 2014, Jackson 2015). I n vitro functional studies provide some evidence that the p.Arg280Cys variant ma y impact protein function (Weichert 2011). However, these types of assays may no t accurately represent biological function. This variant has been reported in Cl inVar (Variation ID: 318566) and has been identified in 30/111616 European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute. org/; dbSNP rs201299260). Computational prediction tools and conservation analys is suggest that the p.Arg280Cys variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, the cli nical significance of the p.Arg280Cys variant is uncertain. ACMG/AMP Criteria ap plied: PP3, PS3_Supporting, PM3_Supporting, BP2. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 15, 2023	Variant summary: ABCA3 c.838C>T (p.Arg280Cys) 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. The variant allele was found at a frequency of 0.00017 in 250570 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ABCA3 causing Pulmonary surfactant metabolism dysfunction (0.00017 vs 0.0011), allowing no conclusion about variant significance. c.838C>T has been reported in the literature in individuals affected with Pulmonary surfactant metabolism dysfunction (Somaschini_2007, Turcu_2013, Jackson_2015). These reports do not provide unequivocal conclusions about association of the variant with Pulmonary surfactant metabolism dysfunction. Co-occurrences with a pathogenic variant has been reported (ABCA3 c.4765C>T, p.Q1589X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in partial disruption of normal activity. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/likely pathogenic, n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pulmonary alveolar proteinosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 08, 2015

The p.R280C variant (also known as c.838C>T), located in coding exon 5 of the ABCA3 gene, results from a C to T substitution at nucleotide position 838. The arginine at codon 280 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was first reported in an infant with neonatal respiratory distress who passed away at 2 days of age; a second alteration was not identified (Somaschini M et al. J. Pediatr. 2007; 150:649-53, 653.e1). This alteration was identified in conjunction with p.E690G in an individual with respiratory distress; however, information on the phase (cis/trans) of the two alterations was not provided (Williamson M and Wallis C Pediatr. Pulmonol. 2014; 49:299-301). A report of a female neonate with respiratory distress and radiological confirmation of surfactant deficiency also detected this alteration in cis with a nonsense pathogenic mutation along with another mutation in trans (Jackson T etl al. J Perinat. 2015;35:231-232). In our own internal cohort, this alteration was also detected in cis with a nonsense mutation in one patient. Functional studies showed this mutation can lead to partial retention of the ABCA3 protein in the endoplasmic reticulum (ER) and induce apoptosis of lung epithelial cells (Weichert N et al. Respir. Res. 2011; 12:4). Based on the available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	3.5	H;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.94
MVP		0.96
MPC		0.99
ClinPred		0.90	D
GERP RS		5.6
Varity_R		0.77
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs201299260; hg19: chr16-2369617;