rs398122386

Variant names:

• chr19-50408817-TCTC-T
• rs398122386
• NM_002691.4:c.1812_1814delCTC

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_002691.4(POLD1):​c.1812_1814delCTC​(p.Ser605del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.000000684 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S604S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.18
• Publications: 29 publications found

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

POLD1 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_002691.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-50408817-TCTC-T is Pathogenic according to our data. Variant chr19-50408817-TCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 60775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1812_1814delCTC	p.Ser605del	disruptive_inframe_deletion	Exon 15 of 27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1812_1814delCTC	p.Ser605del	disruptive_inframe_deletion	Exon 15 of 27	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461698 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727172

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mandibular hypoplasia-deafness-progeroid syndrome Pathogenic:5

Apr 20, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong -

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 04, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Inframe deletion located in a nonrepeat region: predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23770608, 30388038). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 23770608, 26172944, 26350127, 28521875). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000060775 /PMID: 23770608). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Apr 18, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 22, 2019

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:2

Jan 09, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1812_1814delCTC variant in the POLD1 gene is a recurrent pathogenic variant which has been reported several times in association with MDPL (Weedon et al., 2013; Lessel et al., 2015; Reinier et al., 2015). This variant results in an in-frame deletion of a single Serine residue, denoted p.Ser605del. The c.1812_1814delCTC variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The amino acid residue removed by this variant is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret c.1812_1814delCTC as a pathogenic variant. -

May 01, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLD1-related disorder Pathogenic:1

Dec 15, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.1812_1814delCTC variant is predicted to result in an in-frame deletion (p.Ser605del). This variant is the most frequently reported genetic cause of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome and has been reported de novo in the vast majority of affected individuals (Weedon et al. 2013. PubMed ID: 23770608; Lessel et al. 2015. PubMed ID: 26172944; Sasaki et al. 2018. PubMed ID: 29199204; Wang et al. 2018. PubMed ID: 30023403; Yu et al. 2021. PubMed ID: 33369179). This variant is located within the polymerase active site of POLD1, and in vitro functional studies have demonstrated that this variant leads to a total loss of polymerase activity and moderately reduced 3' exonuclease activity (~40%) compared to wild type (Weedon et al. 2013. PubMed ID: 23770608; Oh et al. 2020. PubMed ID: 31944473). Additional in vitro studies also reported a delayed response to DNA damage and increased rates of telomere shortening compared to wild type (Fiorello et al. 2018. PubMed ID: 30388038; Murdocca et al. 2021. PubMed ID: 33618333). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org) and is interpreted as pathogenic by multiple sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/60775/). Of note, this variant is located outside the 3' exonuclease domain associated with increased colorectal cancer risk and, to our knowledge, has not been reported in association with polyposis or colorectal cancer. Therefore, this variant is interpreted as pathogenic for MDPL syndrome but is considered a variant of uncertain significance for colorectal cancer susceptibility. -

Colorectal cancer, susceptibility to, 10 Pathogenic:1

Nov 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.1812_1814del, results in the deletion of 1 amino acid(s) of the POLD1 protein (p.Ser605del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect POLD1 protein function (PMID: 23770608, 30388038). This variant has been observed in individual(s) with clinical features of mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) (PMID: 23770608, 26350127, 28521875, 26172944). ClinVar contains an entry for this variant (Variation ID: 60775). This variant is not present in population databases (ExAC no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 04, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1812_1814delCTC pathogenic mutation (also known as p.S605del) is located in coding exon 14 of the POLD1 gene. This pathogenic mutation results from an in-frame CTC deletion at nucleotide positions 1812 to 1814. This results in the in-frame deletion of a serine at codon 605. This alteration has been reported as de novo in multiple individuals with mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome (Lessel D et al. Hum. Mutat., 2015 Nov;36:1070-9; Reinier F et al. Metab. Clin. Exp., 2015 Nov;64:1530-40; Weedon MN et al. Nat. Genet., 2013 Aug;45:947-50; Chen et al Int. J. Clin. Exp. Med.,2017;10(2):3876-3883). However, c.1812_1814delCTC has not, to our knowledge, been reported in individuals with polyposis or colorectal cancer. This alteration occurs in a highly conserved region of the catalytic subunit of the polymerase, and in vitro functional analysis demonstrated that the catalytic activity of the enzyme is reduced by this alteration (Weedon MN et al. Nat. Genet., 2013 Aug;45:947-50). Based on the available evidence, this alteration is interpreted as a disease causing mutation in association with MDPL syndrome; however, the clinical significance in regards to polyposis and colorectal cancer remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.2
Mutation Taster		=17/83	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs398122386; hg19: chr19-50912074;