Variants in the CLTC gene fall into five broad categories. Each section below gives a full explanation. Silent changes generally have minimal clinical impact, though mild symptoms are occasionally possible; the loss-of-function group (splice-site, frameshift, nonsense) tends to be milder; and missense variants tend to be the most severe.
CLTC Disorders · Source: Nabais Sá et al., Genet Med 2020; NHGRI Genetics Glossary
| # | Type | Also called | Severity tendency | Example (HGVS) | What this typically means for CLTC-ID | Meaning ref. |
|---|---|---|---|---|---|---|
| 1 | Silent mutation | synonymous change | Generally minimal — occasionally mild | c.1416C>T → p.Asp472= [4] | Most silent variants have little or no detectable effect and are classified as benign or as variants of uncertain significance pending more data. However, because the protein-building process itself can be disrupted even when the amino acid letter stays the same, mild clinical features are possible in some cases — particularly when the variant affects a splice signal or alters how efficiently the message is read. If a silent variant is the only finding on your child's report, your geneticist will assess whether it is likely to be functionally significant or not. | [3] |
| 2 | Splice-site variant | a change at a join point in the gene | Loss-of-function group — typically milder | c.835+1G>A [4] | Splice-site variants in CLTC are loss-of-function changes — the cell ends up with roughly half the normal amount of working clathrin (haploinsufficiency). The published case series places these in the milder group: typically developmental delay, intellectual disability, and hypotonia, with a lower likelihood of severe epilepsy or major brain-structure changes than the missense group. | [1] |
| 3 | Frameshift variant | an inserted or deleted letter | Loss-of-function group — typically milder | c.3163del → p.Ile1055Serfs*9 [4] | Frameshift variants are loss-of-function changes (haploinsufficiency). They sit in the same milder clinical group as splice-site and nonsense variants — generally associated with developmental delay, intellectual disability, and hypotonia, with a lower likelihood of the severe epilepsy and brain-structure findings seen with missense variants. | [1] |
| 4 | Nonsense variant | a premature stop signal | Loss-of-function group — typically milder | c.3700C>T → p.Gln1234* [4] | Nonsense variants are loss-of-function changes (haploinsufficiency). The published case series groups them with splice-site and frameshift variants in the milder clinical category — typically developmental delay, intellectual disability, and hypotonia, with a lower risk of severe epilepsy and corpus callosum hypoplasia than missense variants. | [1] |
| 5 | Missense variant | a single-letter change that swaps one protein building block for another | Typically the most severe group | c.2540T>C → p.Leu847Pro [4] | Missense (and the related in-frame) variants are the most clinically severe group in the published CLTC case series. They are more frequently associated with severe intellectual disability, epilepsy, microcephaly (smaller-than-average head size), and hypoplasia of the corpus callosum (the bundle of fibres connecting the two halves of the brain). | [1] |
[1] Nabais Sá MJ et al. (2020). De novo CLTC variants. Genet Med 22(4):797–802. pubmed.ncbi.nlm.nih.gov/31776469/
[2] Helbig KL et al. (2016). CLTC-related NDD. Am J Hum Genet 99(1):134–148.
[3] NHGRI Genetics Glossary — Synonymous Mutation. genome.gov/genetics-glossary/Synonymous-Mutation
[4] ClinVar — CLTC pathogenic variants. ncbi.nlm.nih.gov/clinvar/?term=CLTC%5Bgene%5D