rs606231167

chr19-7555724-C-CGCCA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001166114.2(PNPLA6):c.3058_3061dup(p.Arg1021GlnfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000165 in 1,613,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: PNPLA6 NM_001166114.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 2.08

Genes affected

PNPLA6 (HGNC:16268): (patatin like phospholipase domain containing 6) This gene encodes a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. It is thought to function in neurite outgrowth and process elongation during neuronal differentiation. The protein is anchored to the cytoplasmic face of the endoplasmic reticulum in both neurons and non-neuronal cells. Mutations in this gene result in autosomal recessive spastic paraplegia, and the protein is the target for neurodegeneration induced by organophosphorus compounds and chemical warfare agents. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-7555724-C-CGCCA is Pathogenic according to our data. Variant chr19-7555724-C-CGCCA is described in ClinVar as [Pathogenic]. Clinvar id is 6607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PNPLA6	NM_001166114.2	c.3058_3061dup	p.Arg1021GlnfsTer38	frameshift_variant	24/32	ENST00000600737.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PNPLA6	ENST00000600737.6	c.3058_3061dup	p.Arg1021GlnfsTer38	frameshift_variant	24/32	1	NM_001166114.2	P3

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000124 AC: 31 AN: 249798 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135350

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1461530 Hom.: 0 Cov.: 33 AF XY: 0.000180 AC XY: 131 AN XY: 727106

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.000216

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74310

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000140

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia 39 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Arg983Glnfs*38) in the PNPLA6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PNPLA6 are known to be pathogenic (PMID: 24355708). This variant is present in population databases (rs764267161, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia, Gordon-Holmes syndrome, Boucher-Neuhauser syndrome, and Laurence-Moon syndrome (PMID: 18313024, 24355708, 25480986). ClinVar contains an entry for this variant (Variation ID: 6607). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Paris Brain Institute, Inserm - ICM	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Feb 13, 2020	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 05, 2020	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. This variant is also referred to as c.2946_2947_insCAGC, c.3084_3085insGCCA, and c.3091_3092insAGCC in published literature. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2022	Has been reported previously (as c.2946_2947insCAGC or c.3084_3085insGCCA in some reports due to use of alternate nomenclature) in the compound heterozygous state with a second PNPLA6 variant in multiple individuals with spasticity and other PNPLA6-related symptoms (Ranier et al., 2008; Synofzik et al., 2014; O'Neil et al., 2019); Fibroblasts from two affected siblings demonstrated significantly reduced NTE special activity (Hein et al., 2010); Frameshift 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; This variant is associated with the following publications: (PMID: 35069422, 25480986, 25574898, 23733235, 24355708, 31135245, 33726816, 18313024, 27535533, 34531397, 34256108, 35947152, 3963113, 8053762, 20603202) -

PNPLA6-related disorder Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 07, 2018	The PNPLA6 c.2944_2947dupAGCC (p.Arg983GlnfsTer38) variant results in a frameshift predicted to result in premature termination of the protein. The variant is also referred to in the literature as c.3084_3085insGCCA (p.Arg1031GlufsTer38). The p.Arg983GlnfsTer38 variant has been reported in at least three studies in which it is found in a compound heterozygous state with a missense variant in at least seven patients with a range of phenotypes, two of whom are siblings (Rainier et al. 2008; Synofzik et al. 2014; Hufnagel et al. 2015). The two siblings presented with progressive spastic paraplegia and distal muscle wasting (Rainer et al. 2008). The affected individuals reported by Synofzik et al. (2014) were diagnosed with sporadic ataxia and Gordon Holmes syndrome respectively while the three reported by Hufnagel et al. (2015) presented with Laurence-Moon syndrome. The variant is absent from 405 controls and is reported at a frequency of 0.000485 in the European American population of the Exome Sequencing Project. The p.Arg983GlnfsTer38 variant is predicted to result in the truncation of a large part of the catalytic domain of the protein (Rainier et al. 2008). Based on the potential impact of frameshift variants and the collective evidence, the p.Arg983GlnfsTer38 variant is classified as pathogenic for PNPLA6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 12, 2022	Variant summary: PNPLA6 c.2944_2947dupAGCC (p.Arg983GlnfsX38), which has also been referred to in the literature as c.2946_2947insCAGC (p.S982fs1019), c.3084_3085insGCCA (p.Arg1031GlufsX38), and c.3091_3092insAGCC (p.Arg1031fsX38), results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00012 in 249798 control chromosomes, predominantly at a frequency of 0.00025 within the Non-Finnish European subpopulation in the gnomAD database. c.2944_2947dupAGCC has been reported in the literature in the compound heterozygous state in multiple individuals affected with PNPLA6-Related Disorders including spastic paraplegia, sporadic ataxia, Gordon Holmes syndrome, Oliver-McFarlane syndrome and Laurence-Moon syndrome (e.g. Rainier_2008, Synofzik_2014, Hufnagel_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found reduced enzyme activity (approximately 60% of normal) in fibroblasts from affected compound heterozygous individuals and also reduced activity (approximately 40% of normal) in unaffected carriers of the variant (Hein_2010). Eight submitters have provided assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Laurence-Moon syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

Trichomegaly-retina pigmentary degeneration-dwarfism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2015

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2021

The c.2944_2947dupAGCC (p.R983Qfs*38) alteration, located in exon 27 (coding exon 25) of the PNPLA6 gene, consists of a duplication of AGCC at position 2944, causing a translational frameshift with a predicted alternate stop codon after 38 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in multiple individuals with PNPLA6-related disorders and a second alteration in PNPLA6; however, the phase of the alterations was unclear (Rainier, 2008; Synofzik, 2013; Hufnagel, 2015; Kmoch, 2015; O'Neil, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Laurence-Moon syndrome;C1848745:Trichomegaly-retina pigmentary degeneration-dwarfism syndrome;C1859093:Ataxia-hypogonadism-choroidal dystrophy syndrome;C2677586:Hereditary spastic paraplegia 39 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 09, 2022

- -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 13, 2021

- -

Ataxia-hypogonadism-choroidal dystrophy syndrome Other:1

not provided, no classification provided

literature only

GeneReviews

-

Reported across the PNPLA6 disorders phenotypic spectrum -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs606231167; hg19: chr19-7620610;