Submissions for variant NM_000492.4(CFTR):c.473G>A (p.Ser158Asn)

dbSNP: rs397508725

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Mendelics	RCV000757874	SCV000886391	uncertain significance	Cystic fibrosis	2018-11-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781275	SCV000919188	uncertain significance	not specified	2024-06-25	criteria provided, single submitter	clinical testing	Variant summary: CFTR c.473G>A (p.Ser158Asn) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 249072 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (7.2e-05 vs 0.013), allowing no conclusion about variant significance. c.473G>A has been reported in the literature in individuals affected with Cystic Fibrosis, including at least one compound heterozygous and one homozygous occurrence (e.g. Hicks_2003, Sharma_2009, Najafi_2019, da Silva Filho_2021, Zampoli_2021, Vaidyanathan_2022). However, the variant has also been reported to co-occur in cis with a known pathogenic variant in a CF patient (Hicks_2003). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect resulted in approximately 12.97% of normal chloride channel conductance relative to wild type (e.g., Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 12820707, 20551465, 24440239, 30760291, 18782298, 35857025, 34350279, 32819855, 38388235). ClinVar contains an entry for this variant (Variation ID: 618959). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757874	SCV000947343	pathogenic	Cystic fibrosis	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 158 of the CFTR protein (p.Ser158Asn). This variant is present in population databases (rs397508725, gnomAD 0.06%). This missense change has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 30760291; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.605G>A. ClinVar contains an entry for this variant (Variation ID: 618959). 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 CFTR protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000757874	SCV002027354	uncertain significance	Cystic fibrosis	2021-09-05	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000757874	SCV002073088	uncertain significance	Cystic fibrosis		criteria provided, single submitter	clinical testing	The missense variant p.S158N in CFTR (NM_000492.4) has been reported previously in both trans (Sharma N et al) and in cis with a delta F508 where another variant in trans was not detected (Hicks K et al). The missense variant c.473G>A (p.S158N) in CFTR (NM_000492.4) is observed in 18/30330 (0.0593%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The p.S158N missense variant is predicted to be damaging by both SIFT and PolyPhen2. The serine residue at codon 158 of CFTR is conserved in all mammalian species. The nucleotide c.473 in CFTR is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Since it has been detected in cis with deltaF508 variant in one patient, it's independent pathogenic potential is unclear and hence has been classified as Uncertain Significance.
Ambry Genetics	RCV000757874	SCV003855900	uncertain significance	Cystic fibrosis	2023-02-10	criteria provided, single submitter	clinical testing	The p.S158N variant (also known as c.473G>A and c.605G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 473. The serine at codon 158 is replaced by asparagine, an amino acid with highly similar properties. This alteration was reported along with p.F508del in the compound heterozygous state in an individual with chronic cough, sweat chloride level of 64 mmol/L and pancreatic insufficiency (Sharma N et al. Ann Hum Genet, 2009 Jan;73:26-33). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV001835951	SCV004121247	uncertain significance	CFTR-related disorder	2023-01-24	criteria provided, single submitter	clinical testing	The CFTR c.473G>A variant is predicted to result in the amino acid substitution p.Ser158Asn. This variant has been reported in the compound heterozygous state in an individual with cystic fibrosis and in the homozygous state in an individual with failure to thrive, delayed growth, muscle weakness, dehydration and polyuria (Sharma N et al 2008. PubMed ID: 18782298; Najafi M et al 2019. PubMed ID: 30760291). This variant has been reported in cis with the p.Phe508del pathogenic variant in an unaffected sibling of an individual with cystic fibrosis, in whom a second variant was not found (Hicks K et al 2003. PubMed ID: 12820707). This variant has also been reported in the heterozygous state in an individual with chronic pancreatitis ( Supplementary Table 1, Midha S et al 2010. PubMed ID: 20551465). This variant is not present in the CFTR2 database and to our knowledge, no functional studies are available in the literature. This variant is reported in 0.059% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117171152-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003472278	SCV004213379	likely pathogenic	Bronchiectasis with or without elevated sweat chloride 1	2024-01-24	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV004576966	SCV005060942	uncertain significance	Hereditary pancreatitis		criteria provided, single submitter	clinical testing	The missense c.473G>A (p.Ser158Asn) variant in the CFTR gene has been observed in individual(s) with clinical features of cystic fibrosis (Najafi, Maryam et al., 2019). The variant has been reported previously in both trans (Sharma N et al, 2009) and in cis with a delta F508 where another variant in trans was not detected (Hicks K et al, 2003). This variant is reported with the allele frequency (0.007%) in the gnomAD Exomes. It is submitted to ClinVar as Pathogenic/Uncertain Significance (multiple submissions). The amino acid Serine at position 158 is changed to a Asparagine changing protein sequence and it might alter its composition and physico-chemical properties. The serine residue at codon 158 of CFTR is conserved in all mammalian species. The amino acid change p.Ser158Asn in CFTR is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. Since it has been detected in cis with deltaF508 variant in one patient, it's independent pathogenic potential is unclear and hence has been classified as Uncertain Significance.
Natera, Inc.	RCV001835951	SCV002080146	uncertain significance	CFTR-related disorder	2020-12-04	no assertion criteria provided	clinical testing
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000757874	SCV002754553	uncertain significance	Cystic fibrosis	2022-10-18	no assertion criteria provided	clinical testing