Entering edit mode
6.4 years ago
dr.spear
•
0
hello everybody I am a doctor who is not specialized in genetics , but I have run this test for my son who has a neurological issue and the results came out with significant findings in the KIDINS220 gene , the technical description of the mutation was hard for me to read obviously , I will quote it here and hopefully someone can explain to me the codes in details ( type of mutation, location on chromosome , number of bases involved ,nonsense or missense ...):
KIDINS220 pS1463X : p.Ser1463Ter (TCA>TGA) : c.43888 C>G in exon 30 in the KIDINS220 gene
For more information visit: http://varnomen.hgvs.org/recommendations/protein/. There is an issue as well in this representation. One of the earlier representations (HGVS) include stop codon as x. But later on it was modified to
*. In OP, p.Ser1463Ter (TCA>TGA) stop representation (Ter) is correct, where as in pS1463X, it is incorrect (IMHO). It should have beenpS1463*. A stop codon is represented by Ter (*) in HGVS p-syntax.Might be says that the mutation has occured in exon 30 in the KIDINS220 gene that converted Serine to Stop codon. However, the mutation is due to the conversion of Cytosine (C) to Guanine (G)
No threonine... Termination codon.
I think for a real conclusion you should consult with an expert and not with strangers online without any experience in genetic counseling.
Although we can superficially tell you what this notation means, none of us can give you an answer to the question what the effect and consequences of this are. Genotype-phenotype correlation is hard. Except for a subgroup of clear monogenic diseases, for many many mutations, we don't really know what they do, or how they affect a clinical phenotype. You need functional work for that.
You may want to look for publications in which this mutation was investigated in depth if those exist.
From my investigations, I don't believe this variant has been reported in the literature.
@Emily_Ensembl me neither , I have been unable to find relevant reports, but I would appreciate it if you could give the names of online databases that i could use for such search
I found the gene in Ensembl and looked at the cDNA sequence. I used the line numbering to find the appropriate position, and since it's not highlighted, that tells me that there's no variant at that locus in the database.
I am not actually asking for clinical interpretation , I am only looking technical explanation of the written codes , if I could find someone in the real world to do that for me I wouldn't have had to ask online
thank you very much for all the useful info. I believe the letters "p,S,X" in pS1463X ,and letter "c" in c 43888 , are not arbitrary, could anyone elaborate please on each letter's meaning ?
pS1463X:
p = protein, it's telling you that it's giving you information about the protein.
S = serine. This is the reference amino acid at position 1463.
X = termination codon. This tells you at at position 1463 in the protein, the serine was replaced by a stop codon in your son, which means that the protein (if translated) would be truncated at this point. It may, however, not be translated, as the mRNA would instead be degraded by nonsense mediated decay, resulting in no protein whatsoever. Note that as a chromosome 2 gene, your son will likely also have a functional copy of this protein (unless you've been told otherwise).
The same information is said with three-letter amino acid codes as p.Ser1463Ter. Not sure why they wrote it twice.
@Emily_Ensembl
this has stirred a huge debate between me and the counselor I was referred to, who appears to have a less-than-basic knowledge of genetics ! the mutation is heteroyzgous , I would really appreciate if you could tell me of a test or procedure that can tell if one or two copies are functioning and if the truncated protein is being translated ( assuming that you have some level of clinical knowledge of the relevant field , if not , please accept my apologies )
I think the dominant/recessive thing is an oversimplification. Many genes are able to compensate if their opposite number is missing or broken, but not always. There may be haploinsufficiency, which is where a certain amount of protein is needed, and one copy of the gene is just not able to make enough. This is more likely if you get nonsense-mediated decay.
I suspect that this is not the case for you, since the premature stop codon is in the final exon; the NMD pathway is looking for stops in earlier exons so stops in the final exon evade it. In this case, what is possibly happening is that the non-functional protein is interfering with the function of the other protein. This protein interacts with many other proteins to carry out its function. If the non-functional protein is still there and is interacting with these proteins instead of the functional one, but is unable to carry out its function there, then the whole pathway can be disrupted, particularly if it forms irreversible complexes – all those other proteins are basically knocked out.
A Western Blot should be able to detect the presence of the two proteins, if there is an available antibody. The wildtype protein is 220kDa and I think the truncated one should be ~160kDa, so you would see a size difference. You would need an antibody to this protein though, and these are not always available.