rs1554125752

Positions:

• chr6-35506146-C-CG

Variant summary

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

The NM_003322.6(TULP1):​c.855_856insC​(p.Val286ArgfsTer98) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,212 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: TULP1 NM_003322.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -1.08

Genes affected

TULP1 (HGNC:12423): (TUB like protein 1) This gene encodes a member of the tubby-like gene family (TULPs). Members of this family have been identified in plants, vertebrates, and invertebrates. TULP proteins share a conserved C-terminal region of approximately 200 amino acid residues. The protein encoded by this gene is thought to play a role in the physiology of photoreceptors. Mutations in this gene are associated with recessive juvenile retinitis pigmentosa and Leber congenital amaurosis-15. [provided by RefSeq, Nov 2016]

LOC124901309 (HGNC:):

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 6-35506146-C-CG is Pathogenic according to our data. Variant chr6-35506146-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TULP1	NM_003322.6	c.855_856insC	p.Val286ArgfsTer98	frameshift_variant	10/15	ENST00000229771.11	NP_003313.3
LOC124901309	XR_007059561.1	n.76-2075dup		intron_variant, non_coding_transcript_variant
TULP1	NM_001289395.2	c.696_697insC	p.Val233ArgfsTer98	frameshift_variant	9/14		NP_001276324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.855_856insC	p.Val286ArgfsTer98	frameshift_variant	10/15	1	NM_003322.6	ENSP00000229771	P4
TULP1	ENST00000322263.8	c.696_697insC	p.Val233ArgfsTer98	frameshift_variant	9/14	1		ENSP00000319414	A2
TULP1	ENST00000614066.4	c.849_850insC	p.Val284ArgfsTer98	frameshift_variant	9/14	5		ENSP00000477534	A2
TULP1	ENST00000373892.4	n.457_458insC		non_coding_transcript_exon_variant	4/6	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000890 AC: 13 AN: 1461212 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726918

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: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2023

This sequence change creates a premature translational stop signal (p.Val286Argfs*98) in the TULP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TULP1 are known to be pathogenic (PMID: 8606774, 10549638, 15024725, 18055821). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TULP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 505327). For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa;C0339527:Leber congenital amaurosis Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 05, 2016

The p.Val286ArgfsX98 variant in TULP1 has not been reported in patients and it w as absent from large population studies. This variant is predicted to cause a fr ameshift, which alters the protein?s amino acid sequence beginning at position 2 86 and leads to a premature termination codon 98 amino acids downstream. This al teration is then predicted to lead to a truncated or absent protein. Biallelic l oss of function in the TULP1 gene has been associated with retinal dystrophy (Le ber congenital amaurosis or juvenile retinitis pigmentosa). In summary, although additional studies are required to fully establish its clinical significance, t he p.Val286ArgfsX98 variant in TULP1 is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1554125752; hg19: chr6-35473923;