ClinVar

Description

The CHD7 p.Thr2112Met variant was identified in the literature however the frequency of this variant in an affected population was not provided. In Felix et al. (2006), the role of the CHD7 gene in non-syndromic cleft lip and palate (CLP) cases was studied by sequencing 184 non-syndromic CLP cases from Iowa and the Philippines (92 samples). The p.T2112M variant was found in one individual with non-syndromic CLP from Iowa and was not identified in the control samples. Overall, there was no reported statistical difference in variants found in cases and controls. The variant was identified in dbSNP (ID: rs758409717) and in the Cosmic database where the variant was confirmed somatically in large intestine tissue (adenocarcinoma) with a FATHMM prediction of pathogenic (score=0.99). The variant was not identified in ClinVar and LOVD 3.0. The variant was identified in control databases in 4 of 248948 chromosomes at a frequency of 0.000016 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6046 chromosomes (freq: 0.000165), African in 1 of 15478 chromosomes (freq: 0.000065), South Asian in 1 of 30600 chromosomes (freq: 0.000033) and European (non-Finnish) in 1 of 112750 chromosomes (freq: 0.000009); it was not observed in the Latino, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. The p.Thr2112 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.