chr17-75758304-A-AC

Variant names:

• chr17-75758304-A-AC
• rs1555747776
• NM_000154.2:c.1012dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000154.2(GALK1):​c.1012dupG​(p.Val338GlyfsTer65) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GALK1 NM_000154.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 5.70
• Publications: 0 publications found

Genes affected

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

GALK1 Gene-Disease associations (from GenCC):

• galactokinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 17-75758304-A-AC is Pathogenic according to our data. Variant chr17-75758304-A-AC is described in ClinVar as Pathogenic. ClinVar VariationId is 551344.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000154.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALK1	NM_000154.2	MANE Select	c.1012dupG	p.Val338GlyfsTer65	frameshift	Exon 7 of 8	NP_000145.1
	GALK1	NM_001381985.1		c.1012dupG	p.Val338GlyfsTer99	frameshift	Exon 7 of 9	NP_001368914.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALK1	ENST00000588479.6	TSL:1 MANE Select	c.1012dupG	p.Val338GlyfsTer65	frameshift	Exon 7 of 8	ENSP00000465930.1
	GALK1	ENST00000225614.6	TSL:2	c.1012dupG	p.Val338GlyfsTer99	frameshift	Exon 7 of 9	ENSP00000225614.1
	GALK1	ENST00000592997.6	TSL:2	c.922dupG	p.Val308GlyfsTer65	frameshift	Exon 7 of 8	ENSP00000464765.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Deficiency of galactokinase Pathogenic:1 Uncertain:1

May 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with GALK1-related conditions (PMID: 10790206). ClinVar contains an entry for this variant (Variation ID: 551344). This variant disrupts the C-terminus of the GALK1 protein. Other variant(s) that disrupt this region (p.Pro362Trpfs*37) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic. This sequence change results in a frameshift in the GALK1 gene (p.Val338Glyfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the GALK1 protein and extend the protein by 9 additional amino acid residues.

Oct 09, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.7
Mutation Taster		=1/199	disease causing

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: rs1555747776; hg19: chr17-73754385;