6-35506146-CG-CGG

Variant names:

• chr6-35506146-C-CG
• rs1554125752
• NM_003322.6:c.855dupC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003322.6(TULP1):​c.855dupC​(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 (★★). Synonymous variant affecting the same amino acid position (i.e. P285P) has been classified as Likely benign. 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
• Publications: 0 publications found

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]

TULP1 Gene-Disease associations (from GenCC):

• retinitis pigmentosa 14

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis 15

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000228559 (HGNC:58100):

LOC124901309 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 6-35506146-C-CG is Pathogenic according to our data. Variant chr6-35506146-C-CG is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 505327.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
TULP1	NM_003322.6	c.855dupC	p.Val286ArgfsTer98	frameshift_variant	Exon 10 of 15	ENST00000229771.11	NP_003313.3
TULP1	NM_001289395.2	c.696dupC	p.Val233ArgfsTer98	frameshift_variant	Exon 9 of 14		NP_001276324.1
LOC124901309	XR_007059561.1	n.76-2075dupG		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TULP1	ENST00000229771.11	c.855dupC	p.Val286ArgfsTer98	frameshift_variant	Exon 10 of 15	1	NM_003322.6	ENSP00000229771.6

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52970

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

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111884

Other (OTH) AF: 0.0000166 AC: 1 AN: 60366

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

Mar 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.1

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

Other links and lift over

dbSNP: rs1554125752; hg19: chr6-35473923;