rs398122386

chr19-50408817-TCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_002691.4(POLD1):c.1812_1814del(p.Ser605del) variant causes a 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. F603F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POLD1 NM_002691.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.18

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 id is 60775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50408817-TCTC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLD1	NM_002691.4	c.1812_1814del	p.Ser605del	inframe_deletion	15/27	ENST00000440232.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLD1	ENST00000440232.7	c.1812_1814del	p.Ser605del	inframe_deletion	15/27	1	NM_002691.4	P1

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

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mandibular hypoplasia-deafness-progeroid syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 22, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 20, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM6 strong -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 18, 2022	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 09, 2017	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -

POLD1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 26, 2019

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). 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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 04, 2017

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122386; hg19: chr19-50912074;