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| Hypogonadotropic hypogonadism (GMS) v5.10 | SEMA3A |
Achchuthan Shanmugasundram changed review comment from: Monoallelic variants: PMID:22416012 (2012) reported a cohort of 120 Kallmann syndrome (KS) patients, of which one propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. The patient, sister and father were reported with pubertal failure and anosmia/ hyposmia, and hypogonadism in the patient and father and primary amenorrhea/ absent breast development in the sister. PMID:22927827 (2012) reported the screening of 386 KS patients for the presence of variants in SEMA3A and identified non-synonymous variants in 24 patients, specifically, a frame-shifting small deletion (D538fsX31) and seven different missense variants (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the variants were found in heterozygous state. Note that some of the patients also harbour variants in other KS genes suggesting that this gene supporting oligogenic inheritance. There is also functional evidence available for seven variants which either resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells. In addition, mutant mice lacking a functional Sema3a-binding domain in Nrp1 also displayed Kallmann syndrome-like phenotype. PMID:32060892 (2020) reported screening of SEMA3A variants in a cohort of Chinese patients with isolated hypogonadotropic hypogonadism (IHH) by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two normosmic IHH (nIHH) and one KS patients, respectively. There is also functional evidence available for all three variants, which indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Biallelic variants: PMID:24124006 (2013) reported a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly. This patient was identified with compound heterozygous SEMA3A variants: 150 kb deletion on 7q21.11 affecting exon 1 of SEMA3A (paternal, healthy carrier) + de novo in-frame exon 9 mutation p.Phe316_Lys317-delinsThrSerSerAsnGlu. PMID:28075028 (2017) reported the identification of a homozygous SEMA3A variant p.Arg203Ter in an 8 year old boy with a pattern of multiple congenital anomalies. The phenotype of this patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Hypogonadotrophic hypogonadism was also noted in the first week of life. PMID:33369061 (2020) reported a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism, and anosmia and the patient harboured a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. Animal models: PMID: 8849723 (1996) generated mutant mice lacking semaphorin III that exhibited reduced cortical neuropil, abnormally oriented neuronal processes, skeletal malformations and, in the few surviving beyond the first postnatal days, pronounced right ventricular hypertrophy and right atrial dilation, whereas heterozygous mice appeared normal. Sources: Literature; to: Monoallelic variants: PMID:22416012 (2012) reported a cohort of 120 Kallmann syndrome (KS) patients, of which one propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. The patient, sister and father were reported with pubertal failure and anosmia/ hyposmia, and hypogonadism in the patient and father and primary amenorrhea/ absent breast development in the sister. PMID:22927827 (2012) reported the screening of 386 KS patients for the presence of variants in SEMA3A and identified non-synonymous variants in 24 patients, specifically, a frame-shifting small deletion (D538fsX31) and seven different missense variants (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the variants were found in heterozygous state. Note that some of the patients also harbour variants in other KS genes suggesting that this gene supporting oligogenic inheritance. There is also functional evidence available for seven variants which either resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells. In addition, mutant mice lacking a functional Sema3a-binding domain in Nrp1 also displayed Kallmann syndrome-like phenotype. PMID:32060892 (2020) reported screening of SEMA3A variants in a cohort of Chinese patients with isolated hypogonadotropic hypogonadism (IHH) by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two normosmic IHH (nIHH) and one KS patients, respectively. There is also functional evidence available for all three variants, which indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Biallelic variants: PMID:24124006 (2013) reported a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly. This patient was identified with compound heterozygous SEMA3A variants: 150 kb deletion on 7q21.11 affecting exon 1 of SEMA3A (paternal, healthy carrier) + de novo in-frame exon 9 mutation p.Phe316_Lys317-delinsThrSerSerAsnGlu. PMID:28075028 (2017) reported the identification of a homozygous SEMA3A variant p.Arg203Ter in an 8 year old boy with a pattern of multiple congenital anomalies. The phenotype of this patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Hypogonadotrophic hypogonadism was also noted in the first week of life. PMID:33369061 (2020) reported a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism, and anosmia and the patient harboured a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. Animal models: PMID: 8849723 (1996) generated mutant mice lacking semaphorin III that exhibited reduced cortical neuropil, abnormally oriented neuronal processes, skeletal malformations and, in the few surviving beyond the first postnatal days, pronounced right ventricular hypertrophy and right atrial dilation, whereas heterozygous mice appeared normal. Sources: Literature |
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| Hypogonadotropic hypogonadism (GMS) v5.10 | SEMA3A | Achchuthan Shanmugasundram Classified gene: SEMA3A as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.10 | SEMA3A |
Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of monoallelic SEMA3A variants with hypogonadotropic hypogonadism/ Kallmann syndrome despite some of the patients harbouring variants from additional KS genes. However, there are only two unrelated patients identified with biallelic variants and hypogonadotropic hypogonadism. Hence, the MOI should be set as 'Monoallelic' and the gene should be promoted to green rating. The 'watchlist_moi' tag has been added to review the gene with any new evidence for biallelic variants. |
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| Hypogonadotropic hypogonadism (GMS) v5.10 | SEMA3A | Achchuthan Shanmugasundram Gene: sema3a has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.9 | SEMA3A |
Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Monoallelic SEMA3A variants are associated with hypogonadotropic hypogonadism 16 with or without anosmia in OMIM (MIM #614897) and the record was last accessed on 04 November 2026. Biallelic variants in this gene are not yet associated with phenotypes in OMIM, but associated with SEMA3A-related skeletal dysplasia in Gene2Phenotype (with 'definitive' rating on the DD panel). |
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| Hypogonadotropic hypogonadism (GMS) v5.9 | SEMA3A | Achchuthan Shanmugasundram Phenotypes for gene: SEMA3A were changed from {Hypogonadotropic hypogonadism 16 with or without anosmia}, OMIM:614897; hypogonadotropic hypogonadism 16 with or without anosmia, MONDO:0013961 to {Hypogonadotropic hypogonadism 16 with or without anosmia}, OMIM:614897; hypogonadotropic hypogonadism 16 with or without anosmia, MONDO:0013961 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hypogonadotropic hypogonadism (GMS) v5.8 | SEMA3A |
Achchuthan Shanmugasundram gene: SEMA3A was added gene: SEMA3A was added to Hypogonadotropic hypogonadism (GMS). Sources: Literature watchlist_moi, Q4_26_promote_green tags were added to gene: SEMA3A. Mode of inheritance for gene: SEMA3A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: SEMA3A were set to 8849723; 22416012; 22927827; 24124006; 28075028; 32060892; 33369061 Phenotypes for gene: SEMA3A were set to {Hypogonadotropic hypogonadism 16 with or without anosmia}, OMIM:614897; hypogonadotropic hypogonadism 16 with or without anosmia, MONDO:0013961 Review for gene: SEMA3A was set to GREEN Added comment: Monoallelic variants: PMID:22416012 (2012) reported a cohort of 120 Kallmann syndrome (KS) patients, of which one propositus was found to have a heterozygous deletion of 213 kb at locus 7q21.11, confirmed by real-time qPCR, deleting 11 of the 17 SEMA3A exons. The patient, sister and father were reported with pubertal failure and anosmia/ hyposmia, and hypogonadism in the patient and father and primary amenorrhea/ absent breast development in the sister. PMID:22927827 (2012) reported the screening of 386 KS patients for the presence of variants in SEMA3A and identified non-synonymous variants in 24 patients, specifically, a frame-shifting small deletion (D538fsX31) and seven different missense variants (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the variants were found in heterozygous state. Note that some of the patients also harbour variants in other KS genes suggesting that this gene supporting oligogenic inheritance. There is also functional evidence available for seven variants which either resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells. In addition, mutant mice lacking a functional Sema3a-binding domain in Nrp1 also displayed Kallmann syndrome-like phenotype. PMID:32060892 (2020) reported screening of SEMA3A variants in a cohort of Chinese patients with isolated hypogonadotropic hypogonadism (IHH) by whole exome sequencing. Three novel heterozygous SEMA3A variants (R197Q, R617Q and V458I) were identified in two normosmic IHH (nIHH) and one KS patients, respectively. There is also functional evidence available for all three variants, which indicated that R197Q and R617Q variants were ineffective in activating the phosphorylation of FAK in GN11 cells, despite normal production and secretion in HEK293T cells. The V458I SEMA3A had defect in secretion as it was not detected in the conditioned medium from HEK293T cells. Compared with wild type SEMA3A protein, all three SEMA3A mutant proteins were ineffective in inducing the migration of GN11 cells. Biallelic variants: PMID:24124006 (2013) reported a proband with postnatal short stature, skeletal anomalies of the thorax, congenital heart defect and camptodactyly. This patient was identified with compound heterozygous SEMA3A variants: 150 kb deletion on 7q21.11 affecting exon 1 of SEMA3A (paternal, healthy carrier) + de novo in-frame exon 9 mutation p.Phe316_Lys317-delinsThrSerSerAsnGlu. PMID:28075028 (2017) reported the identification of a homozygous SEMA3A variant p.Arg203Ter in an 8 year old boy with a pattern of multiple congenital anomalies. The phenotype of this patients is characterized by postnatal short stature, skeletal anomalies of the thorax, a minor congenital heart or vascular defect, camptodactyly, micropenis, and variable additional anomalies. Hypogonadotrophic hypogonadism was also noted in the first week of life. PMID:33369061 (2020) reported a female patient presenting with skeletal dysplasia, hypogonadotropic hypogonadism, and anosmia and the patient harboured a nonsense variant c.1633C>T (p.Arg555*) and a deletion of exons 15, 16, and 17 in SEMA3A in the compound heterozygous state. Animal models: PMID: 8849723 (1996) generated mutant mice lacking semaphorin III that exhibited reduced cortical neuropil, abnormally oriented neuronal processes, skeletal malformations and, in the few surviving beyond the first postnatal days, pronounced right ventricular hypertrophy and right atrial dilation, whereas heterozygous mice appeared normal. Sources: Literature |
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