Table 3 CF variants identified in five individuals who were not part of the 38 CFTR variant panel

c.374T>C

A heterozygous missense variant was identified NM_000492(CFTR):c.374T>C in exon 4 of the CFTR gene. This substitution is predicted to create a change of an isoleucine to a threonine at amino acid position 125, NP_000483.3(CFTR):p.(IIe125Thr). The amino acid at this position is highly conserved and is not situated in a known functional domain. The Grantham assessment of amino acid properties and conservation indicates that this change is equivocal. In silico software predictions of the pathogenicity of this variant are conflicting. This variant has not been previously observed in our patient cohort, but is listed on the Cystic Fibrosis Mutation Database and no phenotypic information is available. It is cited in several publications as a variant associated with CF and CF-like symptoms in Asian populations. It is present in the ExAC database at a frequency of less than 1% and 1 homozygote has been reported in the East Asian population. Based on the current information, this variant has been classified as a VUS.

c.1364C>T

A heterozygous missense variant was identified NM_000492(CFTR):c.1364C>T in exon 10 of the CFTR gene. This substitution is predicted to create a change of an alanine to a valine at amino acid position 455, NP_000483.3(CFTR):p.(Ala455Val). The amino acid at this position is highly conserved and is not situated in a known functional domain. The Grantham assessment of amino acid properties and conservation indicates that this change is deleterious. In silico software predicts this variant to be disease-causing. This variant has not been previously observed in our patient cohort, and has not been previously reported in other clinical cases. Based on current information, this variant has been classified as a VUS.

c.1438G>A

A heterozygous missense variant was identified NM_000492(CFTR):c.1438G>A in exon 11 of the CFTR gene. This substitution is predicted to create a change of a glycine to a serine at amino acid position 480, NP_000483.3(CFTR):p.(Gly480Ser). The amino acid at this position is highly conserved and is not situated in a known functional domain. The Grantham assessment of amino acid properties and conservation indicates that this change is deleterious. In silico software predicts this variant to be disease causing. This variant has not been previously observed in our patient cohort, but is listed on the Cystic Fibrosis Mutation Database and in a CBAVD patient. Based on current information, this variant has been classified as a VUS.

c.1666A>G

A homozygous missense variant was identified NM_000492(CFTR):c.1666A>G in exon 12 of the CFTR gene. This substitution is predicted to create a change of an isoleucine to a valine at amino acid position 556, NP_000483.3(CFTR):p.(IIe556Val). The amino acid at this position is moderately conserved and is situated in the NBF1 domain. The Grantham assessment of amino acid properties and conservation indicates that this change is unlikely deleterious. In silico software predictions of the pathogenicity of this variant are conflicting. This variant has not been previously observed in our patient cohort, but is listed in the Cystic Fibrosis Mutation Database and in one additional patient with CBAVD. The variant is present in the ExAC database with 12 homozygote individuals in the East Asian population. Based on current information, this variant has been classified as a VUS.

c.3854C>T

A homozygous missense variant was identified NM_000492(CFTR):c.3854C>T in exon 23 of the CFTR gene. This substitution is predicted to create a change of an alanine to a valine at amino acid position 1285, NP_000483.3(CFTR):p.(Ala1285Val). In ClinVar the clinical significance is not provided. This variant has not been previously observed in our patient cohort, but is listed in the Cystic Fibrosis Mutation Database in a CBAVD patient (Asian/Indian patient). In the ExAC database it is present at 0.5% frequency in South Asians. Based on current information, this variant has been classified as a VUS.