Submissions for variant NM_001099287.2(NIPAL4):c.341C>A (p.Ala114Asp)

gnomAD frequency: 0.00077  dbSNP: rs199422217

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254897	SCV000321771	pathogenic	not provided	2020-03-16	criteria provided, single submitter	clinical testing	The majority of individuals homozygous for this variant present with a collodion membrane at birth and develop generalized ichthyosis with erythema and palmoplantar keratoderma, although a lamellar ichthyosis-like phenotype has also been observed (Lefevre et al., 2004); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25458912, 24397709, 29453417, 31168818, 25525159, 17557927, 20016120, 22622417, 15317751, 22258272, 27025581, 29444371, 26762237, 25326635, 31532840)
Eurofins Ntd Llc (ga)	RCV000254897	SCV000342598	pathogenic	not provided	2016-06-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001801	SCV000455918	pathogenic	Autosomal recessive congenital ichthyosis 6	2017-08-31	criteria provided, single submitter	clinical testing	The NIPAL4 c.527C>A (p.Ala176Asp) missense variant has been described as one of the two most common pathogenic variants for congenital ichthyosis, together accounting for up to 90% of disease alleles (Richard et al. 2014). Across a selection of the available literature, the p.Ala176Asp variant has been identified in a homozygous state in 45 patients and in a compound heterozygous state in eight patients (Lefevre et al. 2004; Dahlqvist et al. 2007; Wajid et al. 2010; Li et al. 2012; Palamar et al. 2015; Kiritsi et al. 2015; Diociaiuti et al. 2016). Up to 60% of individuals were born as collodion babies and most had clinical phenotypes consistent with lamellar ichthyosis or nonbullous congenital ichthyosiform erythroderma. The p.Ala176Asp variant was absent from 300 control chromosomes but is reported at a frequency of 0.0019 in the European American population of the Exome Sequencing Project. Epidermal expression of the ichthyin protein in skin biopsies from healthy individuals showed the enzyme predominantly expressed in the upper epidermis, while expression in individuals homozygous for the p.Ala176Asp variant showed protein in the cell periphery and cytoplasm (Li et al. 2012). Based on the evidence p.Ala176Asp variant is classified as pathogenic for congenital ichthyosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Baylor Genetics	RCV000001801	SCV000807612	pathogenic	Autosomal recessive congenital ichthyosis 6	2017-09-01	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 6-month-old female collodion baby with mild micrognathia, microstomia, hypoplastic flexion creases, congenital ichthyosis. Heterozygotes are expected to be asymptomatic carriers.
Revvity Omics, Revvity	RCV000001801	SCV002018335	pathogenic	Autosomal recessive congenital ichthyosis 6	2022-05-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844003	SCV002103582	pathogenic	Lamellar ichthyosis	2023-04-11	criteria provided, single submitter	clinical testing	Variant summary: NIPAL4 c.341C>A (p.Ala114Asp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00065 in 245384 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NIPAL4 causing Lamellar Ichthyosis (0.00065 vs 0.001), allowing no conclusion about variant significance. c.341C>A has been reported in the literature in multiple individuals affected with Lamellar Ichthyosis, including several homozygotic individuals (examples: Lefevre_2004, Dahlqvist_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000001801	SCV002562747	pathogenic	Autosomal recessive congenital ichthyosis 6	2022-04-07	criteria provided, single submitter	clinical testing	A homozygous missense variant in exon 4 of the NIPAL4 gene that results in the amino acid substitution of Aspartate for Alanine at codon 114 was detected. The observed variant c.341C>A (p.Ala114Asp) has a MAF of 0.05% and 0.07% in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by LRT and MutationTaster2. The reference codon is conserved across mammals. In summary, the variant meets our criteria to be classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001801	SCV002769347	pathogenic	Autosomal recessive congenital ichthyosis 6	2020-05-26	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to aspartic acid (exon 4). (N) 0252 - Variant is homozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (184 heterozygotes, 0 homozygotes). (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (517 heterozygotes, 0 homozygotes). (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (magnesium transporter NIPA domain (PDB, Decipher). (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported as one of the most common pathogenic variants in patients with ichthyosis (ClinVar, PMID: 17557927, PMID: 31046801). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV000254897	SCV003280699	pathogenic	not provided	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 176 of the NIPAL4 protein (p.Ala176Asp). This variant is present in population databases (rs199422217, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive congenital ichthyosis (PMID: 15317751, 17557927, 20016120, 25458912, 26762237, 29444371, 29453417, 31046801, 31168818, 31532840, 34908195, 35412663, 35734965; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as 341C>A (A114N). ClinVar contains an entry for this variant (Variation ID: 1731). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NIPAL4 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000001801	SCV004047044	pathogenic	Autosomal recessive congenital ichthyosis 6	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.341C>A(p.Ala114Asp) variant in NIPAL4 gene has been reported previously in homozygous and compound heterozygous states in multiple individuals affected with congenital ichthyosis (Sitek JC, et al., 2018; Diociaiuti A, et al., 2016; Wajid M, et al., 2010). This variant has been observed to segregate with disease in related individuals. The p.Ala114Asp variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). Computational evidences (Polyphen - Possibly damaging, SIFT - Tolerated and MutationTaster - Disease causing) predicts conflicting evidence on protein structure and function for this variant. The amino acid change p.Ala114Asp in NIPAL4 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 114 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000254897	SCV005196766	pathogenic	not provided	2023-06-02	criteria provided, single submitter	clinical testing
OMIM	RCV000001801	SCV000021957	pathogenic	Autosomal recessive congenital ichthyosis 6	2007-10-01	no assertion criteria provided	literature only
Institute for Human Genetics, University Medical Center Freiburg	RCV000001801	SCV000930510	pathogenic	Autosomal recessive congenital ichthyosis 6	2019-05-16	no assertion criteria provided	clinical testing
Genomics England Pilot Project, Genomics England	RCV000001801	SCV001760158	pathogenic	Autosomal recessive congenital ichthyosis 6		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000254897	SCV001958700	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000254897	SCV001973200	likely pathogenic	not provided		no assertion criteria provided	clinical testing
GeneReviews	RCV001729333	SCV001980663	not provided	Autosomal recessive congenital ichthyosis		no assertion provided	literature only