ClinVar

Description

The MMAB p.Thr222Met variant was not identified in the literature nor was it identified in ClinVar or LOVD 3.0. The variant was identified in dbSNP (ID: rs142070439) and in control databases in 49 of 282836 chromosomes (1 homozygous) at a frequency of 0.0001732 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 36 of 30616 chromosomes (freq: 0.001176), Other in 1 of 7226 chromosomes (freq: 0.000138), European (non-Finnish) in 11 of 129160 chromosomes (freq: 0.000085) and European (Finnish) in 1 of 25104 chromosomes (freq: 0.00004), but was not observed in the African, Latino, Ashkenazi Jewish, or East Asian populations. Although the p.Thr222 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this 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.