ClinVar Genomic variation as it relates to human health

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 484 of the CFTR protein (p.His484Tyr). This variant is present in population databases (rs397508210, gnomAD 0.009%). This missense change has been observed in individual(s) with congenital absence of vas deferens (CAVD), but a second possibly causative variant was not identified (PMID: 10875853). ClinVar contains an entry for this variant (Variation ID: 53257). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.

The p.H484Y variant (also known as c.1450C>T), located in coding exon 11 of the CFTR gene, results from a C to T substitution at nucleotide position 1450. The histidine at codon 484 is replaced by tyrosine, an amino acid with similar properties. This alteration was identified in an individual with congenital absence of the vas deferens (CAVD) (Casals T et al. Hum Reprod, 2000 Jul;15:1476-83). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with congenital absence of the vas deferens (CAVD) in published literature (Casals et al., 2000; Feng et al., 2022); This variant is associated with the following publications: (PMID: 25735457, 35913788, 10875853, 26277102, 18556774)

This recessive variant was identified in a patient with repetitive pancreatitis. The patient harbours also a second variant (see below) in this gene in compound heterozygosity

Variant summary: CFTR c.1450C>T (p.His484Tyr) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 1.2e-05 in 251326 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1450C>T has been reported in the literature in an individual affected with Congenital Bilateral Absence of the Vas Deferens without an identified second allele (Casals_2000). These reports do not provide unequivocal conclusions about association of the variant with Congenital Bilateral Absence Of The Vas Deferens. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 10875853, 18556774, 25735457, 26277102). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.