Submissions for variant NM_052867.4(NALCN):c.3542G>A (p.Arg1181Gln)

dbSNP: rs786201003

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000224736	SCV000599270	pathogenic	Congenital contractures of the limbs and face, hypotonia, and developmental delay	2016-01-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001267339	SCV001445520	pathogenic	Inborn genetic diseases	2018-06-19	criteria provided, single submitter	clinical testing
Invitae	RCV001390781	SCV001592623	pathogenic	not provided	2022-08-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 188046). This missense change has been observed in individual(s) with arthrogryposis/congenital contractures, ataxia, developmental delay, facial dysmorphism, and/or hypotonia (PMID: 25683120, 25864427, 26763878). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1181 of the NALCN protein (p.Arg1181Gln).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001390781	SCV001905593	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001390781	SCV002497678	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	NALCN: PS2, PM2, PS4:Moderate, PP2, PP3, PS3:Supporting
GeneDx	RCV001390781	SCV003842660	pathogenic	not provided	2022-09-13	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: 33060286, 28454995, 34370008, 35256540, 31409833, 25864427, 25683120, 26763878)
Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	RCV000224736	SCV004045798	likely pathogenic	Congenital contractures of the limbs and face, hypotonia, and developmental delay	2022-11-07	criteria provided, single submitter	clinical testing
CHU Sainte-Justine Research Center, University of Montreal	RCV000167764	SCV000207425	likely pathogenic	Intellectual disability with episodic ataxia and congenital arthrogryposis	2015-01-01	no assertion criteria provided	research
University of Washington Center for Mendelian Genomics, University of Washington	RCV000224736	SCV000281697	pathogenic	Congenital contractures of the limbs and face, hypotonia, and developmental delay	2015-05-19	no assertion criteria provided	research