Variant position:  184

Type of variant:  Disease [Disclaimer: Variants classification is intended for research purposes only, not for clinical and diagnostic use. The label disease variant is assigned according to literature reports on probable disease-association that can be based on theoretical reasons. This label must not be considered as a definitive proof for the pathogenic role of a variant.]

Residue change:  From Arginine (R) to Glutamine (Q) at position 184 (R184Q, p.Arg184Gln).

Physico-chemical properties:  Change from large size and basic (R) to medium size and polar (Q)

BLOSUM score:  1

Involvement in disease:  Hydrocephalus due to stenosis of the aqueduct of Sylvius (HSAS) [MIM:307000]: Hydrocephalus is a condition in which abnormal accumulation of cerebrospinal fluid in the brain causes increased intracranial pressure inside the skull. This is usually due to blockage of cerebrospinal fluid outflow in the brain ventricles or in the subarachnoid space at the base of the brain. In children is typically characterized by enlargement of the head, prominence of the forehead, brain atrophy, mental deterioration, and convulsions. In adults the syndrome includes incontinence, imbalance, and dementia. HSAS is characterized by mental retardation and enlarged brain ventricles. {ECO:0000269|PubMed:10797421, ECO:0000269|PubMed:11857550, ECO:0000269|PubMed:12435569, ECO:0000269|PubMed:12514225, ECO:0000269|PubMed:19846429, ECO:0000269|PubMed:20621658, ECO:0000269|PubMed:22344793, ECO:0000269|PubMed:22973895, ECO:0000269|PubMed:24155914, ECO:0000269|PubMed:7562969, ECO:0000269|PubMed:7762552, ECO:0000269|PubMed:7881431, ECO:0000269|PubMed:7920659, ECO:0000269|PubMed:8401576, ECO:0000269|PubMed:8556302, ECO:0000269|PubMed:8929944, ECO:0000269|PubMed:9118141, ECO:0000269|PubMed:9195224, ECO:0000269|PubMed:9268105, ECO:0000269|PubMed:9521424, ECO:0000269|PubMed:9744477, ECO:0000269|PubMed:9832035}. Note=The disease is caused by mutations affecting the gene represented in this entry. L1CAM mutations have also been found in few patients affected by hydrocephalus with Hirschsprung disease, suggesting a role of this gene acting either in a direct or indirect way in the pathogenesis of Hirschsprung disease (PubMed:22344793). {ECO:0000269|PubMed:22344793}.

Variant description:  In HSAS; severe; reduced axon arborization; partial loss of localization at the cell surface; retention in the endoplasmic reticulum; in neurons, restricted to cell bodies and proximal segments of processes; loss of axon guidance and of proper synapse formation, when assayed in a heterologous system.

Other resources:  

• Variant rs137852521 [ dbSNP | Ensembl ]

Variant position:  184

Protein sequence length:  1257

Location on the sequence:   AEPLRIYWMNSKILHIKQDE  R VTMGQNGNLYFANVLTSDNH

Residue conservation: 

Human                         AEPLRIYWMNSKILHIKQDERVTMGQNGNLYFANVLTSDNH

Mouse                         AAPPRIYWMNSKIFDIKQDERVSMGQNGDLYFANVLTSDNH

Rat                           AAPLRIYWMNSKILHIKQDERVSMGQNGDLYFANVLTSDNH

Sequence annotation in neighborhood:  

Genotype-phenotype correlations in L1 syndrome: a guide for genetic counselling and mutation analysis.
Vos Y.J.; de Walle H.E.; Bos K.K.; Stegeman J.A.; Ten Berge A.M.; Bruining M.; van Maarle M.C.; Elting M.W.; den Hollander N.S.; Hamel B.; Fortuna A.M.; Sunde L.E.; Stolte-Dijkstra I.; Schrander-Stumpel C.T.; Hofstra R.M.;
J. Med. Genet. 47:169-175(2010)
Cited for: INVOLVEMENT IN L1 SYNDROME; VARIANTS 26-TYR--GLU-1257 DEL; ASN-37; MET-38; 66-GLN--GLU-1257 DEL; 109-GLN--GLU-1257 DEL; 133-GLU--GLU-1257 DEL; 138-TRP--GLU-1257 DEL; ILE-172; GLY-184; 187-MET--VAL-198 DEL; ASP-254; ARG-276; PRO-313; 366-TRP--GLU-1257 DEL; LYS-369; 423-GLN--GLU-1257 DEL; ARG-480; ASN-516; TYR-516; HIS-525; MET-627; PRO-645; 662-TRP--GLU-1257 DEL; SER-714; ARG-754; 760-ARG--GLU-1257 DEL; 789-GLN--GLU-1257 DEL; 811-TYR--GLU-1257 DEL; 891-TYR--GLU-1257 DEL; 901-ARG--GLU-1257 DEL; 1064-SER--GLU-1257 DEL; ASN-1071 DEL AND GLN-1080; VARIANTS HSAS/MASA SER-179; ARG-335 AND MET-752; VARIANT MASA TYR-202; VARIANTS HSAS GLN-184 AND PRO-415;

X-linked spastic paraplegia (SPG1), MASA syndrome and X-linked hydrocephalus result from mutations in the L1 gene.
Jouet M.; Rosenthal A.; Armstrong G.; Macfarlane J.; Stevenson R.; Paterson J.; Metzenberg A.; Ionasescu V.; Temple K.; Kenwrick S.;
Nat. Genet. 7:402-407(1994)
Cited for: INVOLVEMENT IN MASA; INVOLVEMENT IN HSAS; VARIANTS HSAS GLN-184 AND ARG-452; VARIANT MASA GLN-210;

CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene, L1.
Fransen E.; Lemmon V.; van Camp G.; Vits L.; Coucke P.; Willems P.J.;
Eur. J. Hum. Genet. 3:273-284(1995)
Cited for: VARIANT HSAS/MASA LEU-1194; VARIANTS HSAS GLN-184; TYR-264 AND ARG-452; VARIANTS MASA GLN-210 AND ASN-598;

Nine novel L1 CAM mutations in families with X-linked hydrocephalus.
Macfarlane J.R.; Du J.-S.; Pepys M.E.; Ramsden S.; Donnai D.; Charlton R.; Garrett C.; Tolmie J.; Yates J.R.W.; Berry C.; Goudie D.; Moncla A.; Lunt P.; Hodgson S.; Jouet M.; Kenwrick S.;
Hum. Mutat. 9:512-518(1997)
Cited for: VARIANTS HSAS GLN-184; 439-VAL--THR-443 DEL; CYS-784 AND 936-LEU--LEU-948 DEL;

L1 syndrome mutations impair neuronal L1 function at different levels by divergent mechanisms.
Schaefer M.K.; Nam Y.C.; Moumen A.; Keglowich L.; Bouche E.; Kueffner M.; Bock H.H.; Rathjen F.G.; Raoul C.; Frotscher M.;
Neurobiol. Dis. 40:222-237(2010)
Cited for: CHARACTERIZATION OF VARIANTS HSAS GLN-184 AND LEU-1036; FUNCTION; SUBCELLULAR LOCATION;

Differential effects of human L1CAM mutations on complementing guidance and synaptic defects in Drosophila melanogaster.
Kudumala S.; Freund J.; Hortsch M.; Godenschwege T.A.;
PLoS ONE 8:E76974-E76974(2013)
Cited for: CHARACTERIZATION OF VARIANT VAL-120; CHARACTERIZATION OF VARIANTS MASA GLN-210 AND LYS-309; CHARACTERIZATION OF VARIANTS HSAS GLN-184; TYR-264 AND CYS-1070; MUTAGENESIS OF 1147-LYS--VAL-1153;