rs281865427

Positions:

• chr4-67754305-GA-TT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000406.3(GNRHR):​c.30_31delinsAA​(p.Asn10_Gln11delinsLysLys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GNRHR NM_000406.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.44

Genes affected

GNRHR (HGNC:4421): (gonadotropin releasing hormone receptor) This gene encodes the receptor for type 1 gonadotropin-releasing hormone. This receptor is a member of the seven-transmembrane, G-protein coupled receptor (GPCR) family. It is expressed on the surface of pituitary gonadotrope cells as well as lymphocytes, breast, ovary, and prostate. Following binding of gonadotropin-releasing hormone, the receptor associates with G-proteins that activate a phosphatidylinositol-calcium second messenger system. Activation of the receptor ultimately causes the release of gonadotropic luteinizing hormone (LH) and follicle stimulating hormone (FSH). Defects in this gene are a cause of hypogonadotropic hypogonadism (HH). Alternative splicing results in multiple transcript variants encoding different isoforms. More than 18 transcription initiation sites in the 5' region and multiple polyA signals in the 3' region have been identified for this gene. [provided by RefSeq, Jul 2008]

UBA6-DT (HGNC:49083): (UBA6 divergent transcript)

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a topological_domain Extracellular (size 37) in uniprot entity GNRHR_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000406.3
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-67754305-GA-TT is Pathogenic according to our data. Variant chr4-67754305-GA-TT is described in ClinVar as [Pathogenic]. Clinvar id is 189195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GNRHR	NM_000406.3	c.30_31delinsAA	p.Asn10_Gln11delinsLysLys	missense_variant	1/3	ENST00000226413.5
GNRHR	NM_001012763.2	c.30_31delinsAA	p.Asn10_Gln11delinsLysLys	missense_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GNRHR	ENST00000226413.5	c.30_31delinsAA	p.Asn10_Gln11delinsLysLys	missense_variant	1/3	1	NM_000406.3	P1
UBA6-DT	ENST00000500538.7	n.1921-884_1921-883delinsTT		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 24, 2023	This variant is also known as two separate variants, c.30T>A (p.Asn10Lys) and c.31C>A (p.Gln11Lys). This variant, c.30_31delinsAA, is a complex sequence change that results in the deletion of 2 and insertion of 2 amino acid(s) in the GNRHR protein (p.Asn10_Gln11delinsLysLys). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has been observed in individual(s) with Kallman syndrome or hypogonadotropic hypogonadism (PMID: 15240592, 31200363, 34198905; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 189195). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects GNRHR function (PMID: 15240592). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 11, 2022	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 15240592) In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2022	Published functional studies demonstrate a damaging effect on binding ability and inositol phosphate production (Meysing et al., 2004); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15240592, 29419413, 31200363, 23643382, 20696889, 22745237, 34198905, 31589614) -

Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2004

- -

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: rs281865427; hg19: chr4-68620023;