chr14-50613343-C-T

Position:

• chr14-50613343-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_015915.5(ATL1):​c.715C>T​(p.Arg239Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ATL1 NM_015915.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:19 O:2
• Conservation: PhyloP100: 2.50

Genes affected

ATL1 (HGNC:11231): (atlastin GTPase 1) The protein encoded by this gene is a GTPase and a Golgi body transmembrane protein. The encoded protein can form a homotetramer and has been shown to interact with spastin and with mitogen-activated protein kinase kinase kinase kinase 4. This protein may be involved in axonal maintenance as evidenced by the fact that defects in this gene are a cause of spastic paraplegia type 3. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain GB1/RHD3-type G (size 245) in uniprot entity ATLA1_HUMAN there are 38 pathogenic changes around while only 0 benign (100%) in NM_015915.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-50613344-G-T is described in Lovd as [Pathogenic].
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ATL1. . Gene score misZ 2.6313 (greater than the threshold 3.09). Trascript score misZ 3.8383 (greater than threshold 3.09). GenCC has associacion of gene with hereditary sensory and autonomic neuropathy type 1, hereditary spastic paraplegia 3A, neuropathy, hereditary sensory, type 1D.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954
• PP5: Variant 14-50613343-C-T is Pathogenic according to our data. Variant chr14-50613343-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50613343-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATL1	NM_015915.5	c.715C>T	p.Arg239Cys	missense_variant	7/14	ENST00000358385.12	NP_056999.2
ATL1	NM_001127713.1	c.715C>T	p.Arg239Cys	missense_variant	8/14		NP_001121185.1
ATL1	NM_181598.4	c.715C>T	p.Arg239Cys	missense_variant	7/13		NP_853629.2
ATL1	XM_047431430.1	c.715C>T	p.Arg239Cys	missense_variant	8/15		XP_047287386.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATL1	ENST00000358385.12	c.715C>T	p.Arg239Cys	missense_variant	7/14	1	NM_015915.5	ENSP00000351155	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460004 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726406

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:19 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 3A Pathogenic:12 Other:1

Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 24, 2019	Variant summary: ATL1 c.715C>T (p.Arg239Cys) results in a non-conservative amino acid change located in the Guanylate-binding domain, N-terminal (IPR015894) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes. c.715C>T has been reported in the literature in multiple individuals affected with Spastic paraplegia 3 (Zhao_2001, Novarino_2014). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as evidenced by a disruption in BMPRII trafficking to the cell surface cell surface (example, Zhao_2013). Five 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 19652243, 25637064). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4346). 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 expected to disrupt ATL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 20816793, 23079343). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Aug 04, 2022	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Pathogenic, for Spastic paraplegia 3, autosomal dominant, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: PP1-Strong => PP1 upgraded in strength to Strong (PMID:14607301) (PMID:11685207). PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PS4-Moderate => Recurrent mutation in independent families (PMID:20932283,11685207,20718791,14607301). PS3-Moderate => PS3 downgraded in strength to Moderate (PMID:17321752). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Dec 14, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jul 07, 2023	P1: HP:0001258, P2: HP:0001258 This sequence change in ATL1 is predicted to replace arginine with cysteine at codon 239, p.(Arg239Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the GB1/RHD3-type G domain. There is a large physicochemical difference between arginine and cysteine. This variant is absent from gnomAD v2.1 and v3.1. This is a recurrent variant that has been reported in at least 15 probands/families with pure hereditary spastic paraplegia, and segregates with disease in multiple families (PMID: 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Functional assays in heterologous systems showed impaired GTPase activity, and altered endoplasmic reticulum and Golgi morphology indicating that this variant impacts protein function (PMID: 16537571, 17321752). Computational evidence is uninformative for the missense substitution (REVEL=0.5). Based on the classification scheme RMH Modified ACMG Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS4, PP1_Strong, PS3_Supporting, PM2_Supporting. -
Pathogenic, criteria provided, single submitter	research	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	Apr 23, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 239 of the ATL1 protein (p.Arg239Cys). This variant is predicted to be disease-causing by standard in silico prediction tools (CADD, SIFT, PolyPhen-2, and MutationTaster). ClinVar contains an entry for this variant (Variation ID: 4346), it’s classified as pathogenic/Likely Pathogenic. This variant is not reported in publicly available databases (1000 Genomes and gnomAD). This is a recurrent variant that has been observed in individuals with autosomal dominant hereditary spastic paraplegia (PMID: 14607301, 15517445, 16612642, 19652243, 20718791, 20932283, 20947813, 25637064). Experimental studies have shown that this missense change affects ATL1 function (PMID: 16537571, 17321752, 20816793, 23079343). -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 31, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2022	Published functional studies indicate that R239C causes protein sequestration in the Golgi complex (Botzolakis et al., 2011); Not observed 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: 15517445, 30778698, 19652243, 11685207, 23079343, 20947813, 20718791, 27260292, 27084228, 20816793, 25761634, 14607301, 31630374, 32277485, 32581362, 31216405, 34015694, 21194679, 23334294) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

Hereditary spastic paraplegia 3A;C3150972:Neuropathy, hereditary sensory, type 1D Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 31, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 06-19-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Spastic paraplegia Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

-

- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	.;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.083	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.4	D;D
REVEL	Uncertain	0.50
Sift	Benign	0.037	D;D
Sift4G	Uncertain	0.054	T;T
Polyphen		0.76	.;P
Vest4		0.86
MutPred		0.87		Loss of disorder (P = 0.0112);Loss of disorder (P = 0.0112);
MVP		0.97
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.79
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs119476046; hg19: chr14-51080061; COSMIC: COSV63296065; COSMIC: COSV63296065;