Submissions for variant NM_001099922.3(ALG13):c.320A>G (p.Asn107Ser)

dbSNP: rs398122394

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Courtagen Diagnostics Laboratory, Courtagen Life Sciences	RCV000056321	SCV000236520	pathogenic	Developmental and epileptic encephalopathy, 36	2015-02-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000289979	SCV000329059	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23934111, 26482601, 25877686, 26633542, 28628100, 28778787, 28940310, 28777499, 31444733, 31440721, 32695065, 32238909, 29186148, 30174244, 25732998, 23033978, 24896178, 24781210, 26138355, 27476654, 25533962, 28867141, 29314763, 29190809, 29588952, 28887793, 32681751, 33410528, 31164858, 28191890, 33643843, 33413482, 32978145, 33734437, 32005694, 31785789, 31069529, 35701389)
Invitae	RCV000056321	SCV000541277	pathogenic	Developmental and epileptic encephalopathy, 36	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 107 of the ALG13 protein (p.Asn107Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with infantile spasms, Lennox-Gastaut syndrome, West syndrome and severe intellectual disability (PMID: 23934111, 24781210, 24896178, 25732998, 26138355, 26482601). In at least one individual the variant was observed to be de novo. This variant is also known as X:110928268 A>G. ClinVar contains an entry for this variant (Variation ID: 66086). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic.
Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences	RCV000056321	SCV000693888	pathogenic	Developmental and epileptic encephalopathy, 36	2017-07-15	criteria provided, single submitter	clinical testing
Undiagnosed Diseases Network, NIH	RCV000056321	SCV000746641	pathogenic	Developmental and epileptic encephalopathy, 36	2017-01-26	criteria provided, single submitter	clinical testing
Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes	RCV000289979	SCV000920487	pathogenic	not provided	2018-05-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000056321	SCV001141999	pathogenic	Developmental and epileptic encephalopathy, 36	2019-05-28	criteria provided, single submitter	clinical testing
Cavalleri Lab, Royal College of Surgeons in Ireland	RCV000056321	SCV001160794	pathogenic	Developmental and epileptic encephalopathy, 36	2019-12-11	criteria provided, single submitter	research	ACMG evidence PS1, PS2, PM2, PP3
CeGaT Center for Human Genetics Tuebingen	RCV000289979	SCV001245933	pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000056321	SCV001429501	pathogenic	Developmental and epileptic encephalopathy, 36	2018-01-25	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001249505	SCV001431660	pathogenic	Intellectual disability	2020-08-03	criteria provided, single submitter	clinical testing	The variant c.320A>G, p.(Asn107Ser) was identified in an individual with neurodevelopmental disorder (NDD) and classified as Pathogenic according to ACMG guidelines. Inheritance for this variant was DNV.The variant likely explains the NDD in this individual.
Génétique des Maladies du Développement, Hospices Civils de Lyon	RCV001263094	SCV001439880	pathogenic	Seizure	2020-10-29	criteria provided, single submitter	clinical testing	Recurrent pathogenic variant.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000289979	SCV001447207	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genomics England Pilot Project, Genomics England	RCV000056321	SCV001760502	pathogenic	Developmental and epileptic encephalopathy, 36		criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000056321	SCV002073062	pathogenic	Developmental and epileptic encephalopathy, 36		criteria provided, single submitter	clinical testing	The missense variant p.N107S in ALG13 (NM_001099922.3) has been reported previously as a recurrent mutation in multiple unrelated individuals (Smith-Packard B et al; Ng BG et al). The variant has been submitted to ClinVar as Pathogenic. The p.N107S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.N107S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The asparagine residue at codon 107 of ALG13 is conserved in all mammalian species. The nucleotide c.320 in ALG13 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002321552	SCV002610690	pathogenic	Inborn genetic diseases	2017-10-30	criteria provided, single submitter	clinical testing	The p.N107S pathogenic mutation (also known as c.320A>G), located in coding exon 3 of the ALG13 gene, results from an A to G substitution at nucleotide position 320. The asparagine at codon 107 is replaced by serine, an amino acid with highly similar properties. This mutation has been detected as a de novo occurrence in several individuals with early onset epileptic encephalopathy, infantile spasms, and severe intellectual disability (de Ligt J et al. N. Engl. J. Med., 2012 Nov;367:1921-9; Allen et al. Nature, 2013 Sep;501:217-21; Michaud JL et al. Hum. Mol. Genet., 2014 Sep;23:4846-58; Dimassi S et al. Clin. Genet., 2016 Feb;89:198-204). In one female patient, X-inactivation studies demonstrated a random pattern of X-inactivation, with no evidence of skewness (Hamici S et al. Eur J Med Genet, 2017 Oct;60:541-547). Based on the supporting evidence, p.N107S is interpreted as a disease-causing mutation.
Fulgent Genetics, Fulgent Genetics	RCV000056321	SCV002778213	pathogenic	Developmental and epileptic encephalopathy, 36	2022-02-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003925015	SCV004741224	pathogenic	ALG13-related disorder	2023-12-18	criteria provided, single submitter	clinical testing	The ALG13 c.320A>G variant is predicted to result in the amino acid substitution p.Asn107Ser. This variant has been reported repeatedly to be causative for Lennox-Gastaut Syndrome, early-onset epileptic encephalopathy, infantile spasms and West syndrome (reported as X:110928268A>G in Allen et al. 2013. PubMed ID: 23934111; Myers et al. 2016. PubMed ID: 27476654; Bastaki et al. 2018. PubMed ID: 28940310). It has been documented as a recurrent de novo variant in female individuals with ALG13-related presentations (e.g. Table 1, Ortega-Moreno et al. 2017. PubMed ID: 29190809; Table 1, Kobayashi et al. 2016. PubMed ID: 26482601). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic.
OMIM	RCV000056321	SCV000087490	pathogenic	Developmental and epileptic encephalopathy, 36	2013-09-12	no assertion criteria provided	literature only
Diagnostic Laboratory, Strasbourg University Hospital	RCV001249505	SCV001423495	pathogenic	Intellectual disability	2016-12-01	no assertion criteria provided	clinical testing
Service de Génétique Moléculaire, Hôpital Robert Debré	RCV001256982	SCV001433528	pathogenic	Rare genetic intellectual disability		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000289979	SCV001928665	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000289979	SCV001952301	pathogenic	not provided		no assertion criteria provided	clinical testing
Yale Center for Mendelian Genomics, Yale University	RCV001849307	SCV002106982	likely pathogenic	Seizure; Microcephaly; Neurodevelopmental delay; Hypotonia	2021-03-18	no assertion criteria provided	literature only