Submissions for variant NM_003709.4(KLF7):c.410C>T (p.Thr137Met)

dbSNP: rs1276619385

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001267563	SCV001445744	pathogenic	Inborn genetic diseases	2024-04-04	criteria provided, single submitter	clinical testing	The c.410C>T (p.T137M) alteration is located in exon 2 (coding exon 2) of the KLF7 gene. This alteration results from a C to T substitution at nucleotide position 410, causing the threonine (T) at amino acid position 137 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/251442) total alleles studied. The highest observed frequency was 0.003% (1/34588) of Latino alleles. This variant has been determined to be the result of a de novo mutation in multiple individuals with similar features such as developmental delay, motor delay, speech delay, gait disturbances, and dysmorphic features (Powis, 2018; DECIPHER; External communication). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001880150	SCV002198708	pathogenic	not provided	2021-05-05	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with a neurodevelopmental condition (PMID: 29251763, Invitae). In at least one individual the variant was observed to be de novo. This sequence change replaces threonine with methionine at codon 137 of the KLF7 protein (p.Thr137Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003128382	SCV002576467	likely pathogenic	Delayed gross motor development; Mild expressive language delay	2023-01-25	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_STR, PS4_SUP, PP3
Baylor Genetics	RCV003147605	SCV003835596	likely pathogenic	KLF7-related neurodevelopmental disorder	2022-05-10	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV005241331	SCV003932230	uncertain significance	KLF7-related disorder	2025-02-07	criteria provided, single submitter	clinical testing	PS2, BS2, PP3
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV004035428	SCV005016481	likely pathogenic	Anxiety; Intellectual disability	2022-07-08	criteria provided, single submitter	clinical testing	Gene is not yet OMIM morbid, but a first cohort is published PMID : 29251763
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789505	SCV005399658	likely pathogenic	Neurodevelopmental disorder	2024-09-22	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Mice deficient in KLF7 had neonatal death and and widespread neurological defects suggesting loss of function, while missense variants at important residues in the CPD motif were show to create a more stable protein that could not be phosphorylated or ubiquitylated suggesting gain of function (PMID: 30838725). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0601 - Variant is located in the well-established functional CPD motif and affects the conserved Thr residue. Functional studies in HEK293T cells showed that a mutant KLF7 with both p.(Thr137Ala) and p.(Ser141Ala) could not be phosphorylated or ubiquitylated leading to a more stable protein (PMID: 30838725). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five de novo individuals with KLF7-related disorders (DECIPHER, PMID: 29251763). Additional pathogenic, likely pathogenic and VUS cases have also been reported in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign