VCV000208024.6 - ClinVar

NM_020533.3(MCOLN1):c.1704A>T (p.Gly568=)

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.

(3)

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.

Uncertain significance

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020533.3(MCOLN1):c.1704A>T (p.Gly568=)

Variation ID: 208024 Accession: VCV000208024.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 19p13.2 19: 7533651 (GRCh38) [ NCBI UCSC ] 19: 7598537 (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	Oct 5, 2015	Mar 23, 2024	Aug 29, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_020533.3:c.1704A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_065394.1:p.Gly568=	synonymous
NC_000019.10:g.7533651A>T
NC_000019.9:g.7598537A>T
NG_013374.1:g.4500A>T
NG_015806.1:g.16042A>T

... more HGVS ... less HGVS

Protein change

Other names

1704A-T

Canonical SPDI

NC_000019.10:7533650:A:T

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA347339 OMIM: 605248.0009 dbSNP: rs751298168 VarSome

Comment on variant

In PMID 17239335 this is given as AF287270.1:g.12426A>T, which maps to the end of exon 13 of MCOLN1 (i.e., NM_020533.2:c.1704A>T). This leads to defective splicing in some percentage of the cDNA, though correct splicing is also observed (shown in PMID 17239335 Fig. 4).

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.
MCOLN1		-	-	GRCh38 GRCh37	839	877

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.
Mucolipidosis type IV	Pathogenic (2)	no assertion criteria provided	Apr 1, 2007	RCV000192303.5
not specified	Uncertain significance (1)	criteria provided, single submitter	Aug 29, 2022	RCV002282024.1

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.
Uncertain significance (Aug 29, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002572417.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 17239335 Comment: Variant summary: MCOLN1 c.1704A>T (p.Gly568Gly) alters a non-conserved nucleotide located close to a canonical splice site (the last intron) and therefore could affect mRNA splicing, … (more) Variant summary: MCOLN1 c.1704A>T (p.Gly568Gly) alters a non-conserved nucleotide located close to a canonical splice site (the last intron) and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. Four predict the variant creates a cryptic 5 donor site. Three predict the variant creates a cryptic 3 acceptor site. At least one publication reports this variant affects mRNA splicing proportionally (11% of the altered splicing form was detected) and results in the deletion of 4 bp at the RNA level, a shift of the reading frame (disrupting at the last 14 aa) (example: Dobrovolny_2006). The variant was absent in 247878 control chromosomes (gnomAD). c.1704A>T has been reported in the literature in-at least one individual who had a differential diagnosis for Mucolipidosis Type 4 (example: Dobrovolny_2006). These data do not allow any conclusion about variant significance. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. (less)
Pathogenic (Apr 01, 2007)	no assertion criteria provided Method: literature only	MUCOLIPIDOSIS IV Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025628.4 First in ClinVar: Apr 04, 2013 Last updated: Mar 23, 2024	Publications: PubMed (1) PubMed: 17239335 Comment on evidence: In a non-Ashkenazi Jewish girl with mucolipidosis IV (ML4; 252650), Dobrovolny et al. (2007) identified compound heterozygosity for 2 mutations in the MCOLN1 gene. One … (more) In a non-Ashkenazi Jewish girl with mucolipidosis IV (ML4; 252650), Dobrovolny et al. (2007) identified compound heterozygosity for 2 mutations in the MCOLN1 gene. One allele carried a c.1704A-T transversion near the 3-prime end of exon 13, resulting in erroneous splicing, a 4-bp deletion, and a predicted protein product with the last 12 amino acids exchanged for 9 different ones. Both normal and pathologic splice forms were detected in skin fibroblasts and leukocytes, with the normal form estimated at 40%, presumably enough to prevent psychomotor retardation. The other allele carried D362Y (605248.0005). The phenotype was unusual in that the symptoms were restricted to the eyes, including corneal clouding and decreased visual acuity. She had no neurologic abnormalities. (less)
not provided (-)	no classification provided Method: literature only	Mucolipidosis type IV Affected status: unknown Allele origin: germline	GeneReviews Accession: SCV000243825.3 First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022	Publications: PubMed (1) PubMed: 17239335 BookShelf: NBK1214 BookShelf: NBK1214 Comment: Near the donor site of intron 13; creates an alternative donor splice site that results in a frameshift.

Comment:

Variant summary: MCOLN1 c.1704A>T (p.Gly568Gly) alters a non-conserved nucleotide located close to a canonical splice site (the last intron) and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5 splicing donor site. Four predict the variant creates a cryptic 5 donor site. Three predict the variant creates a cryptic 3 acceptor site. At least one publication reports this variant affects mRNA splicing proportionally (11% of the altered splicing form was detected) and results in the deletion of 4 bp at the RNA level, a shift of the reading frame (disrupting at the last 14 aa) (example: Dobrovolny_2006). The variant was absent in 247878 control chromosomes (gnomAD). c.1704A>T has been reported in the literature in-at least one individual who had a differential diagnosis for Mucolipidosis Type 4 (example: Dobrovolny_2006). These data do not allow any conclusion about variant significance. One submitter has provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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
Mucolipidosis IV.	Adam MP	-	2021	PMID: 20301393
Mucolipidosis IV: report of a case with ocular restricted phenotype caused by leaky splice mutation.	Dobrovolny R	American journal of ophthalmology	2007	PMID: 17239335

Text-mined citations for rs751298168 ...

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 Mar 23, 2024

ClinVar Genomic variation as it relates to human health

NM_020533.3(MCOLN1):c.1704A>T (p.Gly568=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs751298168 ...