VCV000139512.20 - ClinVar

NM_012079.6(DGAT1):c.751+2T>C

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.

(9)

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_012079.6(DGAT1):c.751+2T>C

Variation ID: 139512 Accession: VCV000139512.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 8q24.3 8: 144318093 (GRCh38) [ NCBI UCSC ] 8: 145541756 (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 11, 2015	Oct 8, 2024	Jun 20, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_012079.6:c.751+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000008.11:g.144318093A>G
NC_000008.10:g.145541756A>G
NG_034192.1:g.13827T>C

Protein change

Other names

IVS8, T-C, +2

Canonical SPDI

NC_000008.11:144318092:A:G

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.

Exome Aggregation Consortium (ExAC) 0.00011

The Genome Aggregation Database (gnomAD), exomes 0.00013

The Genome Aggregation Database (gnomAD) 0.00014

Trans-Omics for Precision Medicine (TOPMed) 0.00015

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00038

Links

dbSNP: rs148665132 ClinGen: CA163225 OMIM: 604900.0001 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.
DGAT1		-	-	GRCh38 GRCh38 GRCh37	560	736

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.
Congenital diarrhea 7 with exudative enteropathy	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Jan 20, 2022	RCV000128413.12
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Feb 2, 2018	RCV001266236.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jun 20, 2024	RCV001382858.9
DGAT1-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 20, 2024	RCV004755776.1

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.
Pathogenic (Apr 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital diarrhea 7 with exudative enteropathy Affected status: yes Allele origin: maternal	Elsea Laboratory, Baylor College of Medicine Accession: SCV001424296.1 First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020	Sex: female Testing laboratory: Org: 1006
Pathogenic (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital diarrhea 7 with exudative enteropathy (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Accession: SCV000807603.2 First in ClinVar: Oct 11, 2015 Last updated: Dec 11, 2022	Publications: PubMed (2) PubMed: 25326635‚ 23114594 Comment: This mutation has been previously reported as disease-causing and was found in two affected individuals in our laboratory, including a homozygote and a compound hetrozygote. … (more) This mutation has been previously reported as disease-causing and was found in two affected individuals in our laboratory, including a homozygote and a compound hetrozygote. Both inidividuals had FTT, diarrhea, significant fat malabsorption. Heterozygotes are expected to be asymptomatic carriers. (less)
Pathogenic (Jun 20, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001804375.4 First in ClinVar: Aug 21, 2021 Last updated: Sep 16, 2024	Comment: Published functional studies demonstrate a damaging effect; specifically, cDNA analysis revealed exon 8 skipping leading to the deletion of 25 amino-acids from the MBOAT domain, … (more) Published functional studies demonstrate a damaging effect; specifically, cDNA analysis revealed exon 8 skipping leading to the deletion of 25 amino-acids from the MBOAT domain, and molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced (PMID: 23114594); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26883093, 23114594, 30095213, 31618753, 31589614) (less)
Pathogenic (Feb 02, 2018)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV001444408.2 First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023	Publications: PubMed (2) PubMed: 23114594‚ 26883093 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian/Belizean
Pathogenic (Jan 08, 2024)	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: SCV001581807.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 23114594‚ 26883093 Comment: This sequence change affects a donor splice site in intron 8 of the DGAT1 gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 8 of the DGAT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs148665132, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with congenital chronic diarrhea (PMID: 23114594, 26883093). It has also been observed to segregate with disease in related individuals. This variant is also known as g.13827T>C and g.145541756A>G. ClinVar contains an entry for this variant (Variation ID: 139512). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects DGAT1 function (PMID: 23114594). Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 23114594). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jan 20, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital diarrhea 7 with exudative enteropathy (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848116.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Publications: PubMed (5) PubMed: 23114594‚ 26883093‚ 30095213‚ 31589614‚ 31618753 Comment: The c.751+2T>C variant in DGAT1 has been reported in 6 individuals with congenital diarrheal disorders (CDD), all of whom carried the variant in the homozygous … (more) The c.751+2T>C variant in DGAT1 has been reported in 6 individuals with congenital diarrheal disorders (CDD), all of whom carried the variant in the homozygous or compound heterozygous state, and segregated with disease in 3 affected siblings from 3 families (Haas 2012 PMID: 23114594, Yourshaw 2014, Niu 2015, Stephen 2016 PMID: 26883093, Schlegel 2018 PMID: 30095213, Ziats 2020 PMID: 31618753). It was also identified in 0.48% (19/3924) of Ashkenazi Jewish chromosomes by the gnomAD (http://gnomad.broadinstitute.org); however, this frequency is consistent with the fact that it is likely to be a founder variant in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (Variation ID 139512). The c.751+2T>C variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been demonstrated to cause altered splicing leading to an abnormal or absent protein (Haas 2012 PMID: 23114594, ). In vitro functional studies provide some evidence that the altered splicing may impact protein stability (Haas 2012 PMID: 23114594, Schlegel 2018 PMID: 30095213). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CDD. ACMG/AMP criteria applied: PVS1_Strong, PM3_Strong, PP1_Strong, PS3_Moderate. (less)
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital diarrhea 7 with exudative enteropathy Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893777.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Dec 03, 2012)	no assertion criteria provided Method: literature only	DIARRHEA 7, PROTEIN-LOSING ENTEROPATHY TYPE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000172090.5 First in ClinVar: Jun 28, 2014 Last updated: Jun 09, 2024	Publications: PubMed (2) PubMed: 23114594‚ 26883093 Comment on evidence: In 2 sibs of Ashkenazi Jewish heritage who presented with neonatal intractable diarrhea (DIAR7; 615863), Haas et al. (2012) detected homozygosity for a T-to-C transition … (more) In 2 sibs of Ashkenazi Jewish heritage who presented with neonatal intractable diarrhea (DIAR7; 615863), Haas et al. (2012) detected homozygosity for a T-to-C transition at the +2 position of intron 8 of the DGAT1 gene (chr8:145,541,756, GRCh37). The predicted result of the mutation, skipping of exon 8 resulting in the deletion of 75 basepairs, was confirmed by RT-PCR. Exon 8 deletion removes 25 amino acids from the highly conserved MBOAT domain of DGAT1 but does not affect putative active site residues. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. Both parents and an unaffected sib were heterozygous for the mutation. This variant was found in 3 individuals from 12,500 control exomes; Haas et al. (2012) estimated the probability of homozygosity to be 1 in approximately 50 to 100 million births. In 2 brothers with congenital protein-losing enteropathy from an Ashkenazi Jewish family (family 2), Stephen et al. (2016) identified homozygosity for the previously reported splice site mutation, which they designated as g.13827T-C (NG_034192.1). The mutation was predicted to result in the in-frame deletion of 25 amino acids (Ala226_Arg250del). The unaffected parents and 2 unaffected sibs were heterozygous for the variant. (less)
Pathogenic (Mar 20, 2024)	no assertion criteria provided Method: clinical testing	DGAT1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362333.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The DGAT1 c.751+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. In the literature, this variant is also reported … (more) The DGAT1 c.751+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. In the literature, this variant is also reported as 145541756 A>G, g.13827T>C, or rs148665132. This variant has been reported in the homozygous state in multiple individuals with congenital chronic diarrhea (Haas et al. 2012. PubMed ID: 23114594; Family 2, Stephen et al. 2016. PubMed ID: 26883093; Schlegel et al. 2018. PubMed ID: 30095213). This variant has also been shown to segregate with disease in the above reported families. Functional analyses have shown that this variant causes skipping of exon 8 and abolishes DGAT1 protein activity (Reported as 145541756 A>G, Haas et al. 2012. PubMed ID: 23114594). This variant is reported in 0.48% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/139512/). Variants that disrupt the consensus splice donor site in DGAT1 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)

Comment:

This mutation has been previously reported as disease-causing and was found in two affected individuals in our laboratory, including a homozygote and a compound hetrozygote. Both inidividuals had FTT, diarrhea, significant fat malabsorption. Heterozygotes are expected to be asymptomatic carriers.

Comment:

Published functional studies demonstrate a damaging effect; specifically, cDNA analysis revealed exon 8 skipping leading to the deletion of 25 amino-acids from the MBOAT domain, and molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced (PMID: 23114594); Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26883093, 23114594, 30095213, 31618753, 31589614)

Comment:

This sequence change affects a donor splice site in intron 8 of the DGAT1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs148665132, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with congenital chronic diarrhea (PMID: 23114594, 26883093). It has also been observed to segregate with disease in related individuals. This variant is also known as g.13827T>C and g.145541756A>G. ClinVar contains an entry for this variant (Variation ID: 139512). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects DGAT1 function (PMID: 23114594). Studies have shown that disruption of this splice site results in skipping of exon 8, but is expected to preserve the integrity of the reading-frame (PMID: 23114594). For these reasons, this variant has been classified as Pathogenic.

Comment:

The c.751+2T>C variant in DGAT1 has been reported in 6 individuals with congenital diarrheal disorders (CDD), all of whom carried the variant in the homozygous or compound heterozygous state, and segregated with disease in 3 affected siblings from 3 families (Haas 2012 PMID: 23114594, Yourshaw 2014, Niu 2015, Stephen 2016 PMID: 26883093, Schlegel 2018 PMID: 30095213, Ziats 2020 PMID: 31618753). It was also identified in 0.48% (19/3924) of Ashkenazi Jewish chromosomes by the gnomAD (http://gnomad.broadinstitute.org); however, this frequency is consistent with the fact that it is likely to be a founder variant in the Ashkenazi Jewish population. This variant has also been reported in ClinVar (Variation ID 139512). The c.751+2T>C variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been demonstrated to cause altered splicing leading to an abnormal or absent protein (Haas 2012 PMID: 23114594, ). In vitro functional studies provide some evidence that the altered splicing may impact protein stability (Haas 2012 PMID: 23114594, Schlegel 2018 PMID: 30095213). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CDD. ACMG/AMP criteria applied: PVS1_Strong, PM3_Strong, PP1_Strong, PS3_Moderate.

Comment:

The DGAT1 c.751+2T>C variant is predicted to disrupt the GT donor site and interfere with normal splicing. In the literature, this variant is also reported as 145541756 A>G, g.13827T>C, or rs148665132. This variant has been reported in the homozygous state in multiple individuals with congenital chronic diarrhea (Haas et al. 2012. PubMed ID: 23114594; Family 2, Stephen et al. 2016. PubMed ID: 26883093; Schlegel et al. 2018. PubMed ID: 30095213). This variant has also been shown to segregate with disease in the above reported families. Functional analyses have shown that this variant causes skipping of exon 8 and abolishes DGAT1 protein activity (Reported as 145541756 A>G, Haas et al. 2012. PubMed ID: 23114594). This variant is reported in 0.48% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and is reported as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/139512/). Variants that disrupt the consensus splice donor site in DGAT1 are expected to be pathogenic. This variant is interpreted as 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
Genotype-phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing.	Ziats MN	Pediatric research	2020	PMID: 31618753
Optimizing clinical exome design and parallel gene-testing for recessive genetic conditions in preconception carrier screening: Translational research genomic data from 14,125 exomes.	Capalbo A	PLoS genetics	2019	PMID: 31589614
Reversible deficits in apical transporter trafficking associated with deficiency in diacylglycerol acyltransferase.	Schlegel C	Traffic (Copenhagen, Denmark)	2018	PMID: 30095213
Congenital protein losing enteropathy: an inborn error of lipid metabolism due to DGAT1 mutations.	Stephen J	European journal of human genetics : EJHG	2016	PMID: 26883093
DGAT1 mutation is linked to a congenital diarrheal disorder.	Haas JT	The Journal of clinical investigation	2012	PMID: 23114594

Text-mined citations for rs148665132 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_012079.6(DGAT1):c.751+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs148665132 ...