VCV000373031.9 - ClinVar

NM_153816.6(SNX14):c.1108G>T (p.Glu370Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_153816.6(SNX14):c.1108G>T (p.Glu370Ter)

Variation ID: 373031 Accession: VCV000373031.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 6q14.3 6: 85547112 (GRCh38) [ NCBI UCSC ] 6: 86256830 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 9, 2017	May 6, 2023	Feb 6, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_153816.6:c.1108G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_722523.1:p.Glu370Ter	nonsense
NM_001297614.3:c.1108G>T	NP_001284543.1:p.Glu370Ter	nonsense
NM_001304479.2:c.952G>T	NP_001291408.1:p.Glu318Ter	nonsense
NM_001350532.2:c.1171G>T	NP_001337461.1:p.Glu391Ter	nonsense
NM_001350533.2:c.1105G>T	NP_001337462.1:p.Glu369Ter	nonsense
NM_001350534.2:c.1105G>T	NP_001337463.1:p.Glu369Ter	nonsense
NM_001350535.2:c.1105G>T	NP_001337464.1:p.Glu369Ter	nonsense
NM_001350536.2:c.976G>T	NP_001337465.1:p.Glu326Ter	nonsense
NM_001350537.2:c.973G>T	NP_001337466.1:p.Glu325Ter	nonsense
NM_001350538.2:c.964G>T	NP_001337467.1:p.Glu322Ter	nonsense
NM_001350539.2:c.949G>T	NP_001337468.1:p.Glu317Ter	nonsense
NM_001350540.2:c.1108G>T	NP_001337469.1:p.Glu370Ter	nonsense
NM_001350541.2:c.1108G>T	NP_001337470.1:p.Glu370Ter	nonsense
NM_001350542.2:c.820G>T	NP_001337471.1:p.Glu274Ter	nonsense
NM_001350543.2:c.817G>T	NP_001337472.1:p.Glu273Ter	nonsense
NM_001350544.2:c.808G>T	NP_001337473.1:p.Glu270Ter	nonsense
NM_001350545.2:c.664G>T	NP_001337474.1:p.Glu222Ter	nonsense
NM_001350546.2:c.664G>T	NP_001337475.1:p.Glu222Ter	nonsense
NM_001350547.2:c.58G>T	NP_001337476.1:p.Glu20Ter	nonsense
NM_001350548.2:c.-48+4G>T		intron variant
NM_001350549.2:c.-48+4G>T		intron variant
NM_001350550.2:c.-48+4G>T		intron variant
NM_001350551.2:c.-48+4G>T		intron variant
NM_001350552.2:c.-76G>T		5 prime UTR
NM_001350553.2:c.-48+4G>T		intron variant
NM_020468.6:c.976G>T	NP_065201.1:p.Glu326Ter	nonsense
NR_146774.2:n.990G>T		non-coding transcript variant
NR_146775.2:n.993G>T		non-coding transcript variant
NR_146776.2:n.1116G>T		non-coding transcript variant
NR_146778.2:n.1248G>T		non-coding transcript variant
NR_146779.2:n.1245G>T		non-coding transcript variant
NC_000006.12:g.85547112C>A
NC_000006.11:g.86256830C>A
NG_047171.1:g.52045G>T

... more HGVS ... less HGVS

Protein change

E370*, E270*, E369*, E274*, E322*, E325*, E222*, E391*, E20*, E273*, E317*, E318*, E326*

Other names

Canonical SPDI

NC_000006.12:85547111:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA3912223 dbSNP: rs201128942 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
SNX14		-	-	GRCh38 GRCh37	289	311

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 6, 2023	RCV000413946.6
Autosomal recessive spinocerebellar ataxia 20	Pathogenic (2)	criteria provided, single submitter	Mar 6, 2019	RCV001808789.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Feb 06, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000491590.5 First in ClinVar: Jan 09, 2017 Last updated: May 06, 2023	Comment: Identified in the compound heterozygous state with another SNX14 variant in a patient with early-onset epileptic encephalopathy in published literature (Tsuchida et al., 2018); Nonsense … (more) Identified in the compound heterozygous state with another SNX14 variant in a patient with early-onset epileptic encephalopathy in published literature (Tsuchida et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28940419, 36305856) (less)
Pathogenic (Mar 06, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive spinocerebellar ataxia 20 Affected status: no Allele origin: germline	Centogene AG - the Rare Disease Company Accession: SCV002059453.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022
Pathogenic (Nov 22, 2017)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003279508.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (2) PubMed: 25439728‚ 25848753 Comment: This sequence change creates a premature translational stop signal (p.Glu370) in the SNX14 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Glu370) in the SNX14 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs201128942, ExAC 0.005%). This variant has not been reported in the literature in individuals with SNX14-related disease. ClinVar contains an entry for this variant (Variation ID: 373031). Loss-of-function variants in SNX14 are known to be pathogenic (PMID: 25439728, 25848753). For these reasons, this variant has been classified as Pathogenic. (less)
not provided (-)	no classification provided Method: phenotyping only	Autosomal recessive spinocerebellar ataxia 20 Affected status: yes Allele origin: paternal	GenomeConnect, ClinGen Accession: SCV002074902.1 First in ClinVar: Feb 11, 2022 Last updated: Feb 11, 2022	Comment: Variant interpreted as Pathogenic and reported on 11-01-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided … (more) Variant interpreted as Pathogenic and reported on 11-01-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Pregnancy history (present) , Failure to thrive (present) , Abnormal facial shape (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of … (more) Pregnancy history (present) , Failure to thrive (present) , Abnormal facial shape (present) , Abnormal skull morphology (present) , Oral-pharyngeal dysphagia (present) , Abnormality of eye movement (present) , Sensorineural hearing loss disorder (present) , Abnormality of the nervous system (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Generalized hypotonia (present) , Seizure (present) , Abnormality of facial musculature (present) , Abnormal muscle physiology (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature (present) , Decreased pulmonary function (present) , Feeding difficulties (present) , Abnormal esophagus morphology (present) , Abnormal large intestine morphology (present) , Abnormality of primary teeth (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: GeneDx Date variant was reported to submitter: 2016-11-01 Testing laboratory interpretation: Pathogenic

Comment:

Identified in the compound heterozygous state with another SNX14 variant in a patient with early-onset epileptic encephalopathy in published literature (Tsuchida et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28940419, 36305856)

Comment:

This sequence change creates a premature translational stop signal (p.Glu370*) in the SNX14 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs201128942, ExAC 0.005%). This variant has not been reported in the literature in individuals with SNX14-related disease. ClinVar contains an entry for this variant (Variation ID: 373031). Loss-of-function variants in SNX14 are known to be pathogenic (PMID: 25439728, 25848753). For these reasons, this variant has been classified as Pathogenic.

Comment:

Variant interpreted as Pathogenic and reported on 11-01-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction.	Akizu N	Nature genetics	2015	PMID: 25848753
Mutations in SNX14 cause a distinctive autosomal-recessive cerebellar ataxia and intellectual disability syndrome.	Thomas AC	American journal of human genetics	2014	PMID: 25439728

Text-mined citations for rs201128942 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_153816.6(SNX14):c.1108G>T (p.Glu370Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201128942 ...