Submissions for variant NM_006087.4(TUBB4A):c.745G>A (p.Asp249Asn)

dbSNP: rs483352809

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255689	SCV000322050	pathogenic	not provided	2023-05-18	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: 34514881, 23582646, 28973395, 30079973, 30350845, 32371413, 32463361, 7983175, 25326635, 24785942, 24706558, 24850488, 25545912, 32005694, 35586607)
Baylor Genetics	RCV000043681	SCV000807291	pathogenic	Hypomyelinating leukodystrophy 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 de novo in a 13-year-old male with a progressive neurological disorder with mild intellectual disability, hypotonia at 17m (resolved), ataxia, spasticity, dystonia, possible seizures, short stature, microcephaly, hyperopia, brain abnormalities.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000043681	SCV001219584	pathogenic	Hypomyelinating leukodystrophy 6	2022-10-05	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects TUBB4A function (PMID: 28973395, 30079973). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TUBB4A protein function. ClinVar contains an entry for this variant (Variation ID: 50985). This missense change has been observed in individual(s) with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID: 23582646, 24706558, 25545912). 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 aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 249 of the TUBB4A protein (p.Asp249Asn). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000255689	SCV001248473	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing
Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	RCV001249621	SCV001423694	pathogenic	Torsion dystonia 4; Hypomyelinating leukodystrophy 6	2019-01-15	criteria provided, single submitter	clinical testing	[ACMG/AMP: PS2, PS3, PM1, PM2, PP2, PP3] This alteration is de novo in origin as it was not detected in the submitted parental specimens (identity confirmed) [PS2], is supported by well-established in vitro or in vivo functional studies to have a damaging effect on protein function or splicing [PS3], is located in a mutational hotspot and/or critical and well-established functional domain [PM1], is absent from or rarely observed in large-scale population databases [PM2], is a missense variant in a gene in which missense variants are a common mechanism of disease [PP2], is predicted to be damaging by multiple functional prediction tools [PP3].
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000255689	SCV001449614	likely pathogenic	not provided	2016-07-07	criteria provided, single submitter	clinical testing
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814029	SCV001755669	pathogenic	Abnormality of the nervous system	2021-07-10	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000255689	SCV002022480	pathogenic	not provided	2020-08-05	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000043681	SCV002072571	pathogenic	Hypomyelinating leukodystrophy 6	2022-01-25	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS3, PM1, PM2_SUP, PP3
3billion	RCV000043681	SCV002521548	pathogenic	Hypomyelinating leukodystrophy 6	2022-05-22	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000050985). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID:23582646, 24706558, 25545912). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genetics and Molecular Pathology, SA Pathology	RCV000043681	SCV002556601	pathogenic	Hypomyelinating leukodystrophy 6	2020-10-29	criteria provided, single submitter	clinical testing	The TUBB4A c.745G>A missense variant is classified as PATHOGENIC (PS4_moderate, PM2, PS2, PP2, PP3) The TUBB4A c.745G>A missense variant is a single nucleotide change in exon 4 of the TUBB4A gene, which is predicted to change the amino acid aspartic acid at position 249 in the protein to asparagine. This recurrent variant has been reported in multiple patients with leukodystrophy, specifically, hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) (PMID:23582646, PMID:24785942) (PS4_moderate). This variant is de novo in this patient and in the majority of reported cases in the literature (PS2). The variant is in dbSNP (rs483352809) but is absent from population databases (PM2). This variant has been reported in ClinVar as pathogenic by multiple other diagnostic laboratories (Variation ID:50985). The variant is a missense variant in a gene with low rate of benign missense variants (PP2). Computational predictions support a deleterious effect on the gene or gene product (PP3).
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV000043681	SCV005187395	pathogenic	Hypomyelinating leukodystrophy 6	2020-12-30	criteria provided, single submitter	clinical testing	This missense variant (c.745G>A, p.Asp248Asn) has not been observed in population databases (gnomAD), but the change has been reported in the literature (PMID 24785942, PMID 23582646, PMID 16707859, PMID 7983175, PMID 24850488, PMID 18466252, PMID 30079973, PMID 28973395). Variant prediction programs suggest a deleterious effect, and this is supported in published functional studies (PMID 30079973, PMID 28973395). It has been seen in 3 unrelated affected individuals in this laboratory.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV000043681	SCV005201015	pathogenic	Hypomyelinating leukodystrophy 6	2023-01-01	criteria provided, single submitter	clinical testing
OMIM	RCV000043681	SCV000071692	pathogenic	Hypomyelinating leukodystrophy 6	2014-05-21	no assertion criteria provided	literature only
Texas Scottish Rite Hospital for Children	RCV000043681	SCV000148341	not provided	Hypomyelinating leukodystrophy 6		no assertion provided	not provided
GeneReviews	RCV000043681	SCV000328453	not provided	Hypomyelinating leukodystrophy 6		no assertion provided	literature only